Molecular and Comparative Genetics of Mental Retardationgenetic MR disorders. Detailed analyses of 1000 Online Mendelian Inheritance in Man (OMIM) database entries and literature searches

Copyright 2004 by the Genetics Society of America

Molecular and Comparative Genetics of Mental Retardation

Jennifer K. Inlow*,1 and Linda L. Restifo*,†,‡,2

*Arizona Research Laboratories Division of Neurobiology, †Department of Neurology, ‡Genetics GraduateInterdisciplinary Program, University of Arizona, Tucson, Arizona 85721-0077

Manuscript received August 14, 2003Accepted for publication November 14, 2003

ABSTRACTAffecting 1–3% of the population, mental retardation (MR) poses significant challenges for clinicians

and scientists. Understanding the biology of MR is complicated by the extraordinary heterogeneity ofgenetic MR disorders. Detailed analyses of �1000 Online Mendelian Inheritance in Man (OMIM) databaseentries and literature searches through September 2003 revealed 282 molecularly identified MR genes.We estimate that hundreds more MR genes remain to be identified. A novel test, in which we distributedunmapped MR disorders proportionately across the autosomes, failed to eliminate the well-knownX-chromosome overrepresentation of MR genes and candidate genes. This evidence argues against ascer-tainment bias as the main cause of the skewed distribution. On the basis of a synthesis of clinical andlaboratory data, we developed a biological functions classification scheme for MR genes. Metabolic path-ways, signaling pathways, and transcription are the most common functions, but numerous other aspectsof neuronal and glial biology are controlled by MR genes as well. Using protein sequence and domain-organization comparisons, we found a striking conservation of MR genes and genetic pathways across the�700 million years that separate Homo sapiens and Drosophila melanogaster. Eighty-seven percent have oneor more fruit fly homologs and 76% have at least one candidate functional ortholog. We propose thatD. melanogaster can be used in a systematic manner to study MR and possibly to develop bioassays fortherapeutic drug discovery. We selected 42 Drosophila orthologs as most likely to reveal molecular andcellular mechanisms of nervous system development or plasticity relevant to MR.

MENTAL RETARDATION (MR) is a common form clinical conditions affect such large numbers of childrenof cognitive impairment affecting between 1 and and young adults and yet have no effective pharmacolog-

3% of the population of industrialized countries (Roele- ical therapy. One reason for the lack of drug treatmentsveld et al. 1997; Aicardi 1998). Although there is de- is the limited understanding of the molecular and cellu-bate over the definition and classification of MR (Leo- lar bases for MR.nard and Wen 2002), it is often defined by an IQ of Many environmental and genetic factors can cause�70, with deficits in adaptive skills included as diagnos- MR, including premature birth, prenatal infections,tic criteria (Luckasson et al. 1992; Daily et al. 2000). chromosomal abnormalities, and single-gene mutationsBehavioral and cognitive therapies can help mentally (Kinsbourne and Graf 2000). An etiology can be estab-retarded patients reach their maximum potential (Bat- lished in 60–75% of cases of severe MR, but only inhaee 2001; Butler et al. 2001), but they are not curative 38–55% of mild cases. Estimates of genetic causes ofand often focus on treating habit disorders, aggression, severe MR range from 25 to 50% (McLaren and Bry-or self-injurious behavior that can accompany MR son 1987). There are two categories of hereditary MR.(Long and Miltenberger 1998; Dosen and Day 2001). Isolated MR with no other consistent defining featuresMR due to congenital hypothyroidism is now largely is known as nonspecific or nonsyndromal MR. To date,preventable through screening and hormone replace- all but one of these (Molinari et al. 2002) are X-linked,ment (Gruters et al. 2002). Aside from this, the only but other autosomal genes may have eluded identifica-molecular-based therapeutic approaches are dietary re- tion because of the considerably greater difficulty ofstrictions and supplements for inborn errors of metabo- mapping disorders to autosomal loci. MR also occurs,lism such as phenylketonuria (Dashman and Sansaricq with variable penetrance and expressivity, as a pheno-1993; Levy 1999; Kabra and Gulati 2003). Few, if any, typic feature of numerous hereditary syndromes. The

challenge of understanding the biological bases of he-reditary MR is heightened by its enormous genetic het-

1Present address: Department of Chemistry, Indiana State University, erogeneity and the limited knowledge of cellular pheno-Terre Haute, IN 47809. types in the brains of mentally retarded individuals.

2Corresponding author: Arizona Research Laboratories Division of Recent rapid progress in human genetics, however, hasNeurobiology, 611 Gould-Simpson Bldg., 1040 E. 4th St., University ofArizona, Tucson, AZ 85721-0077. E-mail: [email protected] provided us with an opportunity for a comprehensive

Genetics 166: 835–881 ( February 2004)

836 J. K. Inlow and L. L. Restifo

MATERIALS AND METHODSanalysis of the biochemical and cellular processes under-lying the MR phenotype. A search for “mental retarda- Databases and bioinformatics tools: The OMIM databasetion” in the Online Mendelian Inheritance in Man [McKusick-Nathans Institute for Genetic Medicine, Johns

Hopkins University and National Center for Biotechnology(OMIM) database (Hamosh et al. 2002) yields �1000Information (NCBI), National Library of Medicine; Hamoshentries, suggesting that hundreds of human genes canet al. 2002] was accessed online (http://www.ncbi.nlm.nih.mutate to a MR phenotype. We conducted a detailed gov/entrez/query.fcgi?db�OMIM) to search for genes and

analysis to determine how many MR genes have been mental retardation disorders. BLASTP (Altschul et al. 1997)molecularly identified and what molecular and biologi- at the NCBI (http://www.ncbi.nlm.nih.gov/BLAST/) and

the Homophila Human-Disease-to-Drosophila-Gene databasecal functions they encode.(Reiter et al. 2001; http://homophila.sdsc.edu/) were usedControversies over the definition of MR are based onto search for D. melanogaster homologs of the human MR genes.both sociopolitical and biological considerations (Leo- Pairwise sequence alignments were performed with LALIGN

nard and Wen 2002). Narrow definitions of MR restrict (http://www.ch.embnet.org/software/LALIGN_form.html;it to cases of nonprogressive cognitive impairment pres- Huang and Miller 1991). DotPlot and TransMem of the

Accelrys GCG Wisconsin Package were accessed through theent from birth and categorize as “dementia” cases ofArizona Research Laboratories Biotechnology Computing Fa-progressive cognitive deterioration beginning somecility and were used to compare homologous protein se-

time after a period of normal development. Nonethe- quences by dot matrix analysis (Maizel and Lenk 1981) andless, hereditary neurodegenerative disorders are often prediction of transmembrane regions, respectively. The In-

terPro resource for protein families, domains, and sitessaid to cause MR (see Stevenson et al. 2000), even(Apweiler et al. 2001; http://www.ebi.ac.uk/interpro/scan.when the onset is in late childhood or adolescence (e.g.,html) was used to determine and compare the locations ofprogressive epilepsy with mental retardation, one of thefunctional domains in homologous proteins. The Gene Ontol-

neuronal ceroid lipofuscinoses; CLN8). Moreover, the ogy (GO) database (Gene Ontology Consortium 2001) wasdistinction between MR and dementia blurs in disorders accessed online (http://www.geneontology.org/) to deter-

mine the molecular-function classification of MR gene prod-such as Rett syndrome (MECP2), where phenotypesucts. FlyBase (FlyBase Consortium 2002) was accessed on-span a wide spectrum of severity and clinical courseline (http://flybase.bio.indiana.edu/) to obtain information(Hammer et al. 2002). For the purpose of our analysison Drosophila genes. Newly isolated P-element insertions were

of hereditary MR, we chose a broader, albeit less precise, found through the P-Screen Database (http://flypush.imgen.definition that includes progressive disorders with onset bcm.tmc.edu/pscreen/).

Identifying human mental retardation genes throughof cognitive impairment in childhood and, occasionally,OMIM: We searched all OMIM fields on February 21, 2002,as late as adolescence.using the phrase “mental retardation” and reviewed each ofIn parallel with human genetics research, progress in the resulting 1010 entries. To include very mild MR, we also

Drosophila melanogaster genetics and genome sequencing searched for “cognitive impairment” and “learning disability,”(Adams et al. 2000) allows a comparative approach to obtaining 38 additional entries for evaluation. In retrospect,

“developmental delay” and “psychomotor retardation” wouldthe biological study of MR. Not only do homologoushave been useful search phrases as well. Other MR genes weremammalian and fruit fly genes share biological func-identified by periodic literature searches through Septembertions (Padgett et al. 1993; Bonini et al. 1997; Johnston 30, 2003, using NCBI’s PubMed.

et al. 1997; Leuzinger et al. 1998; Nagao et al. 1998; Careful evaluation of individual OMIM search results andDearborn et al. 2002), but also Drosophila provides cross-referencing with literature-search results revealed both

false positives and false negatives. OMIM contains many par-useful models of human disease, including spinocere-tially redundant entries, which makes it impossible to equatebellar ataxia (Warrick et al. 1998), Parkinson’s diseasenumbers of entries obtained from a search for a specific phe-(Feany and Bender 2000), Huntington’s disease (Jack- notype with the number of genes that can mutate to that

son et al. 1998), and type 1 diabetes (Rulifson et al. phenotype. OMIM entries for a genetic disorder or gene are2002). Moreover, neurodegeneration in the Drosophila organized into some or all of the following fields: title, MIM

number, gene map, clinical synopsis, text (literature sum-model of Huntington’s disease can be suppressed bymary), allelic variants, references, and contributors. Whentreatment with a specific peptide (Kazantsev et al.different mutations of a single gene cause distinct disorders,

2002). Hence, we propose that this neurogenetic model there are separate OMIM entries for each disease, but onlysystem can reveal cellular phenotypes responsible for one contains a list of disease-associated alleles (“allelic vari-

ants” field). For example, mutations in the L1CAM gene resulthereditary MR and will provide bioassays for potentialin one of at least three MR disorders (Weller and Gartnerdrug therapies. By searching the Drosophila genome,2001): MASA syndrome (mental retardation, aphasia, shuf-we found candidate functional orthologs for the major- fling gait, and adducted thumbs), HSAS (hydrocephalus due

ity of molecularly identified human MR genes. Several to congenital stenosis of the aqueduct of Sylvius), or SPG1dozen of these genes are most likely to have mutant (spastic paraplegia 1). There is a separate OMIM entry for

each of these disorders and a fourth entry for the L1CAMphenotypes due to primary developmental defects ofgene. There is some text redundancy among the four entries,neurons or glia and thereby provide clues to the causesbut only the L1CAM entry includes the allelic variants field.and treatment of MR due to single-gene mutations. On the basis of this organizational scheme, OMIM searches

Treatment strategies based on the understanding of restricted to entries containing the allelic variants field shouldeliminate redundant results. However, this strategy wouldhereditary MR may be useful for acquired MR as well.

837Molecular Genetics of Mental Retardation

cause false negatives because entries that list allelic variants Identifying Drosophila orthologs of human mental retarda-tion genes: We used bioinformatics tools to determine if thedo not necessarily contain complete phenotype descriptions.

For example, entry 600514, which lists the allelic variants of human MR genes have likely functional orthologs in D. melano-gaster. For MR genes encoding tRNAs, we aligned the humanreelin (RELN), does not contain the phrase “mental retarda-

tion,” whereas entry 257320 for Norman-Roberts type lis- and fly tRNA homologs using LALIGN and calculated thepercentage identity. For each protein-coding MR gene, wesencephaly syndrome due to RELN mutations contains the

search phrase but does not list allelic variants. In principle, searched the D. melanogaster sequences of the NCBI nonredun-dant database with NCBI’s BLASTP. We used an E -value cutoffthe “clinical synopsis” field could offer a useful search strategy

for disease phenotypes, but some are incomplete (e.g., the of 1 � 10�10 (1e -10), a threshold commonly used for human-clinical synopsis for Norman-Roberts lissencephaly does not fly gene comparisons (Fortini et al. 2000; Lloyd et al. 2000;include MR although it is a consistent phenotype of this disor- Reiter et al. 2001). The Homophila database (Reiter et al.der) and many entries have no clinical synopsis at all. 2001) is designed for such comparisons but, due to its organi-

Errors in the clinical synopsis fields also contributed to zational features and infrequent updates, we found it easierthe many (�15%) false-positive entries (see Table 1). For and more reliable to do our own BLAST searches. For oneexample, entries 167200 and 167210 for pachyonychia con- MR gene, we concluded that Drosophila does not have agenita types 1 and 2 include MR in their clinical synopses, biologically meaningful homolog despite a published claimbut the only evidence for MR is in the much rarer type 4 of one. Grunge (FBgn0010825) is the most similar fly gene(Feinstein et al. 1988). Other false positives result from state- to human DRPLA (Zhang et al. 2002), but has a BLASTPments such as “neither [patient] had evidence of mental retar- E -value of 5E-2, which does not meet our threshold. Moreover,dation” (entry 243605). In other entries MR is not a feature sequence similarity is limited to the extreme C terminus andof the disorder being described, but some atypical patients the Grunge protein does not possess the same domain organi-are mentally retarded due to deletion of adjacent genes (e.g., zation as DRPLA.entry 312865). Finally, MR may be mentioned because related For protein-coding MR genes, we also conducted a “reverse”disorders have a MR phenotype. For instance, MR is a pheno- BLASTP search using the top-scoring Drosophila BLASTP re-type of a subset of hereditary spastic paraplegias, so it is men- sult as a query against the human sequences of the NCBItioned in the text of the entries for most forms. Boyadjiev and nonredundant database. A Drosophila gene was consideredJabs (2000) noted similar difficulties in extracting information an ortholog of a human MR gene only if this reverse analysisfrom OMIM. To obtain complete information from OMIM, (sometimes supplemented with dot-matrix plot and protein-one must search in a manner that yields redundant and irrele- domain comparison; see below) revealed that it was morevant entries. This minimizes false negatives, but, to interpret similar to the human MR gene (or a paralog) than to anotherthe search results accurately, one must be willing to review gene. For example, the Drosophila proteins most similar toindividual entries carefully. Even using a broad OMIM search human glial fibrillary acidic protein (GFAP) are the productsstrategy, we missed 45 MR genes that were revealed through of Lamin and Lamin C. A reverse BLASTP search revealedvarious literature search strategies. that, although these two proteins share a single common do-

Functional classification of human mental retardation genes: main with GFAP, they are more similar over their full lengthsWe searched for the 282 MR gene products in the molecular- to members of the human lamin family. In addition, bothfunction category of the GO database and used information human and Drosophila lamins are localized to the nucleusfrom the literature to classify those not yet in the database. (Goldman et al. 2002), whereas GFAP is cytoplasmic (Eng et al.The GO database is composed of three parallel schemes for 2000). Hence, GFAP does not have an ortholog in Drosophila.classifying gene function: biological process, cellular compo- When compared with mammals, Drosophila has relativelynent, and molecular function (Gene Ontology Consortium few duplicated genes (Durand 2003), so in some cases a2001). Each ontology is a hierarchical classification scheme Drosophila gene is the single ortholog of a paralogous set of(directed acyclic graph) of structured vocabulary terms that human genes. For example, FMR1, which causes fragile Xdiffers from a simple hierarchical tree, such as a pedigree, in syndrome, is a member of a gene family that also includes FXR1that each term may be a “child” of multiple independent and FXR2, the autosomal fragile X-related genes. Drosophila“parents.” There are 24 occupied top-level terms in the molec- dfmr1 is the only homologous fly gene, sharing significantular-function ontology, i.e., terms that do not have parents sequence similarity and domain structure with all three humanthemselves. When GO assigned gene products to multiple genes, suggesting that it is the sole ortholog.molecular functions, we chose the most specific term for each. To determine if orthologous genes are likely to share theFor example, we classified the �-subunit of Gs, the adenyl- same molecular and biological functions in humans and flies,ate cyclase-stimulating guanine nucleotide-binding protein we used dot matrix plots (GCG DotPlot) to assess the extent(GNAS), as a “nucleotide-binding protein” rather than as a of protein sequence similarity and searched the InterPro data-“hydrolase,” the other GO assignment. For genes considered base for known functional domains in each protein. GCGby GO to have “unknown function,” we found that most could TransMem was used to predict transmembrane regions inbe provisionally classified on the basis of data in the literature. the human and fly proteins. If the proteins share sequenceThe “biological function(s)” assignments were based on similarity over most of their lengths and have similar organiza-literature reviews for each gene, including neuroimaging, tion of known functional domains, we considered them to begene expression, and neuropathological data from human candidate functional orthologs. In some cases we also consid-patients, as well as studies of wild-type and mutant mice. We ered expression patterns, mutant phenotypes, and subcellularfirst designated the basic cellular process in which the gene is localization. In cases of “computed genes” predicted from theprimarily involved, e.g., cytoskeleton or chromosome struc- Drosophila genome sequence, the absence of experimentalture. We then identified the site of primary organ system func- data made the evaluation of ortholog status more difficult.tion, relative to MR: endocrine system, central nervous system,or neither. For those genes that directly impact central nervoussystem (CNS) development and/or function, we ascertained

RESULTS AND DISCUSSIONthe tissue type (neuron, glia, or blood vessel) and the specificcellular process affected (e.g., cell identity or differentiation).

The 282 mental retardation genes have been molecu-We also considered whether MR caused by mutation of thegene is secondary to toxicity or secondary to energy or fuel deficiency. larly identified: Analysis of OMIM and literature search


TABLE 1

OMIM mental retardation entries

No. of % ofCategory Description entries entries

1 Known gene 254 25.12 Candidate gene 55 5.43 Chromosomal region 98 9.74 Candidate chromosome 26 2.65 Not mapped 416 41.26 Chromosomal abnormality 9 0.97 No MR phenotype 149 14.88 Nonexistent disorder 3 0.3

Total: 1010 100

This table is based on analysis of a search done on February21, 2002.

gene and allelic variants have been identified (thiscategory includes OMIM entries for the MR disordersas well as separate entries describing the genes them-Figure 1.—Diagram of the identification of human mentalselves).retardation genes and their comparison to D. melanogaster

Category 2: The disorder has been mapped to one orgenes. The OMIM searches were performed on February 21,2002. The literature search was completed on September 30, more candidate genes in a chromosomal region (con-2003. tiguous gene deletion syndromes, e.g., Prader-Willi,

are in this category).Category 3: The disorder has been mapped to a chromo-results allows us to present a status report on the genetics

somal region.of MR. From the 1010 OMIM “mental retardation” en-Category 4: The disorder has been mapped to a candi-tries obtained on February 21, 2002, we found 204 hu-

date chromosome.man genes that cause MR either in isolation or as partCategory 5: The disorder has not yet been mapped toof a syndrome. Through literature searches we found

a chromosome.45 additional MR genes whose OMIM entries did notCategory 6: The disorder is caused by a gross chromo-contain the search phrase “mental retardation.” About

somal abnormality and no single gene determines thea quarter of these “false-negative” entries contained theMR phenotype (Down syndrome is one example).phrases “psychomotor retardation” and/or “develop-

Category 7: MR is not a phenotype of the disorder.mental delay.” To include disorders causing very mildCategory 8: The disorder does not exist.MR, we also searched OMIM for entries containing “cog-

nitive impairment” or “learning disability” but not “men- The number of OMIM entries in category 1 (“knowntal retardation.” Most of these 38 entries describe adult- gene”), 254, is greater than the number of genes, 204,onset, progressive cognitive impairment disorders, but because of OMIM database redundancy (see materialsliterature review identified 4 of them as MR genes. Fi- and methods). The nearly 600 OMIM entries in catego-nally, literature searches between March 2002 and Sep- ries 2–5 represent MR disorders in which the causativetember 30, 2003 revealed 29 recently identified MR genes were unknown (see below). Of the 29 recentlygenes for a total of 282 human genes known to cause discovered MR genes, half had “advanced” from “candi-MR (Figure 1). On the basis of these and subsequent date gene” (1 gene), “chromosomal region” (9 genes),publications, we estimate that new MR genes are being or “unmapped” (5 genes) categories. Thirteen repre-identified at a rate of 1–2 per month. The appendix sent new loci that can cause a known disorder. Onelists the 282 MR genes in alphabetical order by their (FKRP) causes a form of muscular dystrophy, not pre-gene symbols, along with their associated MR disorders, viously associated with MR, that had been in category 7.chromosomal locations, OMIM numbers, and other in- Entries in category 6 (“chromosomal abnormality”)formation explained below. As will be discussed in later describe bona fide MR disorders, but we have not consid-sections, the MR genes control an extraordinary range ered them further in this analysis because they appearof molecular and cellular functions. to involve many genes (e.g., Shapiro 1999). It remains

We classified the 1010 OMIM “mental retardation” to be determined whether individual genes that contrib-entries, based on data available in spring 2002, ac- ute to MR in cases of aneuploidy or other chromosomalcording to the following scheme (Table 1):

defects can mutate to an MR phenotype individually.The 149 OMIM entries in category 7 (“no MR pheno-Category 1: The disorder has been mapped to a specific


type”) represent false positives in which MR is not a Fourth, mutations in genes controlling thyroid devel-opment or function rarely cause MR in industrializedphenotype (see materials and methods). Most ofsocieties because of neonatal screening and treatmentthese false-positive errors could be eliminated by thefor hypothyroidism (Gruters et al. 2002). Hence, whileadoption of a controlled vocabulary for OMIM clinicala dozen known genes have been associated with MRsynopses, with the previously mentioned caveat that MRsecondary to hypothyroidism (appendix), mutations indefinitions vary. The three entries in category 8 (“non-other similar genes may not have had the “opportunity”existent disorders”) do not represent distinct clinicalto reveal whether they would cause MR in untreatedentities, and one was subsequently removed from thepatients. Finally, syndromal MR genes for which the MROMIM database.phenotype has very low penetrance present a significantWith �600 OMIM MR entries in categories 2–5 (Ta-ascertainment challenge. For example, eight DNA re-ble 1), it is obvious that many more MR genes remain topair genes/disorders are associated with MR in a modestbe identified—but how many? Some of these disorders,fraction of patients. It seems likely that more such disor-particularly those in categories 4 (“candidate chromo-ders (e.g., the rarer Fanconi anemia complementationsome”) and 5 (“not mapped”), are likely to representgroups) have MR as a bona fide phenotype, but, presum-MR genes that are already known. This is because ofably because the phenotype depends on chance somaticboth practical difficulties in mapping human pheno-mutations during brain development (Gilmore et al.types and the phenomenon of phenotypic divergence;2000), it is difficult to confidently assign MR to theiri.e., different mutant alleles of the same gene causeclinical descriptions.distinct MR disorders (e.g., different DKC1 mutations

Given all these considerations, predicting the trueresult in dyskeratosis congenita or Hoyeraal-Hreidars-number of human MR genes is difficult. A complete andson syndrome). Similarly, novel MR genes that remainaccurate count may be beyond the capacity of medicalto be identified may each explain more than one disor-science to determine directly. We believe that 282 repre-der, especially within the large unmapped group.sents substantially less than half of the total. It is easyHence, this set of OMIM entries is likely to representto imagine that human MR genes could number �1000.�595 genes.

X-linked mental retardation genes: To date, eightOn the other hand, what MR disorders might beX-linked genes are known to cause exclusively nonspe-“missing” from our analysis? First, we know that somecific MR (MRX genes), and 31 X-linked genes causegenes, or their corresponding disorders, are present inexclusively syndromal forms of MR (Table 2). Nonspe-the OMIM database but fail to appear in MR-relatedcific MR has been the focus of much attention, in partsearch results because of inconsistent use of terminologybecause of the idea that genes with “pure” behavioral

in the medical literature, curatorial errors, or differingphenotypes, unaccompanied by gross brain abnormali-

opinions on what constitutes mental retardation (see ties or other organ system defects, may provide greatermaterials and methods). Second, MR mutations oc- insight into the molecular basis of cognition than thecurring in small families likely represent a large number syndromal MR genes (Chelly 1999; Toniolo 2000).of genes not yet listed in OMIM. Some families never Indeed, several MRX genes figure prominently in Rho-reach the attention of medical genetics research teams. type G-protein pathways (ARHGEF6, GDI1, OPHN1,Small pedigrees represent significant challenges for gene PAK3, FGD1; Ramakers 2002) or are regulated by neu-mapping, even on the X chromosome (Ropers et al. ronal activity (PAK3, IL1RAPL1, RSK2, TM4SF2; Boda2003). The X-Linked Mental Retardation Genes Update et al. 2002). However, with the discovery that mutationsSite (http://xlmr.interfree.it/home.htm; Chiurazzi et of five MR genes can cause either nonspecific or syndro-al. 2001) lists 57 nonspecific MR families and 110 mal MR (Table 2), the distinction between the two cate-X-linked MR syndromes for which the genes remain gories may not be as meaningful as originally proposedelusive. However, only 80 OMIM entries described (see discussion in Frints et al. 2002).X-linked MR disorders (syndromes and nonspecific) for For RSK2 (RPS6KA3), the phenotype difference iswhich genes have not been identified (Table 1, X-linked explained by allele type and severity. The R383W mu-entries in categories 2–4). tation that causes MRX19 is a partial loss-of-function

A third “missing” or underrecognized category is com- allele, encoding a protein with 20% of wild-type kinaseposed of essential genes of which most deleterious muta- activity (Merienne et al. 1999). In contrast, null mu-tions cause early prenatal lethality and only exceptional tations of RSK2 cause Coffin-Lowry syndrome withalleles with specific molecular consequences permit via- prominent skeletal and connective tissue involvementbility along with an MR phenotype. In genetic model (Hanauer and Young 2002). For several genes, thesystems, complementation testing can easily show that a structure-function relationships are inferred but not di-viable “memory mutation” is allelic to mutations causing rectly demonstrated. The T1621M mutation of ATRXearly death with profound neuroanatomical defects (also known as XH2 or XNP) causes nonspecific MR(e.g., Pinto et al. 1999), but comparable mapping stud- in the mild-to-moderate range (Yntema et al. 2002).

Although residue 1621 is within the highly conservedies are much more difficult in humans.


TABLE 2

X-linked mental retardation genes

Type of MR No. of XLMR % of XLMRdisorder genes genes Gene symbols (see also appendix)

Nonspecific only 8 18.2 ARHGEF6, FACL4, FMR2, GDI1, IL1RAPL1, OPHN1, PAK3, TM4SF2Syndromal only 31 70.5 All other X-linked genes in the appendixBoth 5 11.4 ARX, ATRX, FGD1, MECP2, RSK2Total 44 100

XLMR, X-linked mental retardation.

SNF2-related domain, it is not conserved, suggesting Chromosomal distribution of human mental retarda-tion genes: Of the 282 human MR genes, 11 are encodedthat some alterations at that site are compatible with

partial function of this nuclear protein involved in chro- by the mitochondrial genome. Figure 2A shows thechromosomal distribution of the 271 nuclear MR genesmatin structure and transcription regulation. Missense

mutations just 7 and 12 residues upstream, however, compared to the chromosomal distribution of all knownand predicted human genes based on the human ge-cause a more severe, syndromal phenotype with hemato-

logic, skeletal, and genital defects (Gibbons et al. 1995), nome sequence (Venter et al. 2001). While �4% ofknown and predicted genes are on the X chromosome,suggesting greater disruption of ATRX function. A vari-

ety of FGD1 mutations, most of which truncate the en- �16% of the MR genes reside there—a fourfold over-representation. In contrast, the distribution of MRcoded putative Rho GEF, cause Aarskog-Scott syndrome,

which includes highly penetrant skeletal and genital genes among the autosomes roughly parallels their rela-tive gene contents (Figure 2A). An even greater X-chro-anomalies but infrequent, and only mild, MR. In con-

trast, one particular missense mutation in a region of mosome overrepresentation is found among the MRdisorders mapped to candidate loci (6-fold), chromo-unknown function, P312L, causes severe, fully penetrant

nonspecific MR (Lebel et al. 2002). somal regions (14-fold), and chromosomes (15-fold),which correspond to categories 2, 3, and 4, respectively,Genotype-phenotype relationships are even more

complex for MECP2 and ARX. Within and among Rett of Table 1.It has been proposed that the human X chromosomesyndrome families, females with MECP2 mutations show

great clinical heterogeneity, with X-inactivation patterns contains a disproportionately high density of genes forcognitive ability (Lehrke 1972; Turner and Parting-and mutation sites believed to explain the severity differ-

ences (Cheadle et al. 2000; Hammer et al. 2002). In ton 1991). This proposal generated controversy as wellas speculation concerning possible underlying evolution-addition, at least seven different missense mutations in

MECP2, scattered over the length of the protein, cause ary mechanisms, including the intriguing suggestionthat female mate selection for high male intelligencenonspecific MR (Orrico et al. 2000; Couvert et al.

2001); several of these are very close to sites of Rett- helped accelerate the rapid rise of human cognitiveabilities (Turner 1996; Zechner et al. 2001). The identi-syndrome-causing missense mutations (Cheadle et al.

2000; Hammer et al. 2002). For ARX, identical muta- fication of numerous MRX genes and X-linked MR syn-dromes (Chiurazzi et al. 2001) seemed to support thetions, resulting in polyalanine tract expansion of this

homeodomain protein, caused nonspecific MR in one proposal. Opponents, however, argued that all X-linkedrecessive mutations are simply easier to map and identifyfamily, but distinct neurological syndromes (West or

Partington or MR with hypsarrhythmia) in various other because their phenotypes are revealed in hemizygousmales (Morton 1992; Lubs 1999). Countering this viewfamilies (Stromme et al. 2002). This suggests a major

effect of genetic background on ARX phenotypes. Other is an OMIM-based analysis (Zechner et al. 2001) show-ing a 7.2-fold X-chromosome bias for MR genes, whereasARX mutations cause a unique lissencephaly syndrome

with abnormal genitalia (Kitamura et al. 2002). genes causing common morphological phenotypes(polydactyly, cleft palate, facial dysplasia, skeletal dyspla-Complex genotype-phenotype relationships are also

a feature of some autosomal MR disorders (e.g., FGFR1, sia, and growth retardation) have, on average, only a2.4-fold X-chromosome bias. [Zechner et al. (2001) didGLI3, PEX1, PTEN, PTPN11). On the basis of X-linked

MR, it is possible that some alleles of the one known not take OMIM errors, such as false positives and nega-tives, into consideration, but such errors may be compa-autosomal nonspecific MR gene (PRSS12; Molinari et

al. 2002) will be found to cause a syndromal MR pheno- rable across phenotypes.]To take this question one step further, we askedtype. Conversely, autosomal genes presently known to

cause MR syndromes may be able to mutate to a nonspe- whether the apparent X-chromosome overrepresenta-tion among the molecularly identified human MR genescific MR phenotype.


(Figure 2A) would disappear if we accounted for theplausible possibility that numerous autosomal loci are“hiding” among the unmapped MR genes (representedby the OMIM entries in category 5, Table 1). We at-tempted to overcome the ascertainment bias that favorsidentification of X-linked genes by making simplifyingassumptions that maximize the estimate of autosomalMR genes and minimize the estimate of X-linked MRgenes. First, we assumed that one OMIM entry equalsone gene. Second, for the unmapped MR disorders(category 5, Table 1), we assumed that each representsa different, novel autosomal gene and that these aredistributed in proportion to the overall gene distribu-tion on those chromosomes (Venter et al. 2001). Third,for those disorders whose genes map to chromosomalregions and candidate chromosomes (categories 3 and4, Table 1), we assumed that there will be no newX-linked genes, i.e., that each potential X-linked geneis identical to an X-linked gene already known to causeMR. However, all candidate genes (category 2, Table1), including the X-linked genes, were assumed to benew MR genes.

Even when these very conservative (i.e., biased towardautosomal) assumptions are used to estimate the chro-mosomal distribution of the unknown MR genes, a 1.9-fold overrepresentation of MR genes on the X chromo-some remains (Figure 2B). This result supports thehypothesis that the X chromosome contains a dispro-portionately high density of genes influencing cognitiveability. One caveat is the possibility discussed above thatmany autosomal MR genes may be so rare or difficultto study that they never appear in the medical literatureand, hence, in OMIM. We also agree with the suggestionof Lubs (1999) that resolution of this issue would beenhanced by analyzing genome-wide brain expressiondata and by searching for allelic variation in single genesresponsible for the high end of the intelligence spec-trum.

D. melanogaster homologs of human mental retarda-tion genes: We found that 87% of known MR genes(246/282) have at least one Drosophila homolog witha BLASTP E-value of 1 � 10�10 or better (Figure 1;Figure 2.—Chromosomal distribution of human mentalappendix). Similarly, Reiter et al. (2001) found thatretardation genes and D. melanogaster orthologs. (A) The chro-

mosomal distribution of the 271 molecularly identified nu- 75% of �1400 human disease genes, representing allclear MR genes is compared to the chromosomal distribution major disease categories, have Drosophila homologs atof all nuclear, protein-coding human genes based on human this level of sequence similarity. More important, 76%genome sequence analysis (Venter et al. 2001). Note the

(213) of the MR genes, including syndromal and non-striking overrepresentation of X-linked MR genes. (B) Thesyndromal types, have at least one Drosophila orthologpredicted chromosomal distribution of known and potential

MR genes based on maximizing the assignment of genes to (see materials and methods and appendix). In fact,autosomes (see results and discussion), compared to all a handful of the human genes were named for theirnuclear human genes as in A. The X-chromosome overrepre- Drosophila orthologs, in most cases prior to their identi-sentation has been reduced, but remains almost twofold. (C)

fication as MR genes (ASPM : abnormal spindle-like, micro-The chromosomal distribution of the Drosophila MR genecephaly-associated ; EMX2 : homolog 2 of empty spiracles ;orthologs is compared to the chromosomal distribution of

all nuclear, protein-coding Drosophila genes on the basis of PTCH : homolog of patched ; PTCH2 : homolog 2 of patched ;Drosophila genome sequence analysis (Adams et al. 2000; see SHH : sonic hedgehog ; SIX3: homolog 3 of sine oculis).FlyBase at http://flybase.bio.indiana.edu/ for Release 3). Dro- The appendix lists the Drosophila homologs and or-sophila homologs of human MR genes that are not orthologs

thologs of the MR genes, their FlyBase accession num-were not included in this analysis.


bers, and the BLASTP E-values (see also Figure 1 for the GO database (Figure 3; appendix; see materialsand methods). The MR genes are distributed over aoverview). As discussed below, several dozen Drosophilabroad range of functions, indicating that disruption oforthologs (designated “¶” in the appendix) are primeany of a wide array of molecular processes can impaircandidates for cellular and molecular study of MR. Sev-brain function so as to cause MR. Several categories areenteen MR genes (6%; designated with asterisk) haveprominently represented, such as enzymes (143 genes;one or more homolog(s) that may be orthologs, but it51%), mediators of signal transduction (32 genes; 12%)is not possible to make a determination on the basis ofand transcription regulation (19 genes; 7%), bindingsequence analysis in the absence of experimental data.proteins (23 genes; 8%), and transporters (21 genes;Another 16 MR genes (6%; in brackets) have one or8%). Enzymes, especially those expressed in accessiblemore Drosophila homolog(s) that are not orthologs onperipheral tissues, make gene identification easier thanthe basis of reverse BLAST results or other sequencethat for many other proteins, so their relative represen-analysis (see materials and methods). There are 36tation may decline as new MR genes are discovered.MR genes (13%) with no Drosophila homolog, al-Other categories with smaller numbers of MR genesthough this number may decline as final gene identifi-include cell adhesion molecule, structural molecule,cation for the Drosophila genome is completed.motor protein, tRNAs, apoptosis regulator, chaperone,Some of the Drosophila genes are functional or-and enzyme regulator. GO classifies �9% of the MRthologs of human MR genes on the basis of experimen-genes (25) in the “unknown function” category, buttal data. For instance, mutations of dfmr1, the Drosoph-published data suggest functions for all but 10 of themila ortholog of fragile X mental retardation 1 (FMR1; Wan(see appendix).et al. 2000), cause specific disruptions of neuronal mor-

Within the GO molecular-function ontology, top-levelphology (Zhang et al. 2001; Morales et al. 2002; Leecategories include fundamental molecular functionset al. 2003; C. Michel, R. Kraft, B. Hassan and L.(e.g., binding activity, of which there are many subcate-Restifo, unpublished results) and behavioral defectsgories), as well as others related to a specific cellular(Dockendorff et al. 2002; Inoue et al. 2002). Geneticprocess (e.g., cell adhesion molecule), and in manyand biochemical data suggest that Drosophila dFMR1cases, genes could be assigned to more than one. Thisis a regulator of translation (Zhang et al. 2001; Ishizukamakes classification, analysis, and comparison to otheret al. 2002), as has been shown for mammalian FMRPsets of genes somewhat difficult. We did not classify any(Kaytor and Orr 2001; Laggerbauer et al. 2001; Maz-MR gene products as “defense/immunity proteins,” butroui et al. 2002; Zalfa et al. 2003). Although learningIKBKG encodes a subunit of a signal transducer (ourphenotypes of dfmr1 mutant flies have not yet beencategory choice) that regulates NF-�B in the immune

reported, four of the fruit fly MR gene orthologs areand inflammatory response pathway (Wallach et al.

“learning and memory genes” on the basis of behavioral 2002). We also did not use the “translation regulator”data: G protein s�60A (Connolly et al. 1996), the or- category, but EIF2AK3 encodes a kinase (our categorytholog of GNAS; Neurofibromin 1 (Guo et al. 2000), the choice) that indirectly regulates translation by phos-ortholog of NF1; cheerio (see Dubnau et al. 2003, online phorylating eukaryotic translation initiation factor-2supplement), the ortholog of FLNA; and S6kII or igno- (Ma et al. 2002). Similarly, we classified FMR1 as “RNArant (G. Putz, T. Zars, and M. Heisenberg, personal binding,” but considerable data demonstrate that it reg-communication), the ortholog of RSK2. Additional Dro- ulates translation (Jin and Warren 2003). In addition,sophila learning and memory genes have been pro- we could have classified some genes in the “proteinposed as candidates for MR disorders that are not yet stabilization” (e.g., PPGB), cytoskeletal regulator (e.g.,mapped (Morley and Montgomery 2001). TBCE), or “protein tagging” (e.g., UBE3A) categories.

The Drosophila orthologs of the human MR genes However, anticoagulant, antifreeze, antioxidant, chap-do not have a skewed chromosomal distribution (Figure erone regulator, nutrient reservoir, and toxin are top-2C). Approximately 16% of all fly genes and 16% of level categories in which none of the 282 MR genesMR gene orthologs are on the X chromosome. Of the could be placed.first two dozen Drosophila “learning and memory Figure 3 indicates the Drosophila-homolog status ofgenes” identified, almost 50% are X-linked (reviewed in the MR genes in each molecular-function category. TheDubnau and Tully 1998; Morley and Montgomery 213 MR genes with Drosophila ortholog(s) (solid bars)2001). However, the recent isolation of 60 new auto- are distributed among the GO categories in roughlysomal memory genes (Dubnau et al. 2003) indicates the same pattern as that of all the MR genes, with twothat the older results reflect the previous tendency to exceptions. More than half of the “receptor binding”design X-chromosome screens for behavioral and genes (4 of 7) and 36% (9 of 25) of the “unknownneuroanatomical phenotypes. function” MR genes have no Drosophila homolog.

Molecular functions of mental retardation genes: Biological functions of mental retardation genes: WeEach of the 282 MR genes was classified in a single devised a “biological function(s)” classification scheme

for the 282 MR genes that considers both cellular- andmolecular-function category, primarily on the basis of


Figure 3.—Molecular function classification ofmental retardation genes. Genes were classifiedon the basis of GO categories (see materials andmethods). In cases where the top-level parentterms include large numbers of genes (signaltransduction, binding, transcription regulation,enzyme), we show the distribution of genesamong the children terms. For many of the genesthat have not yet been classified by the GO Con-sortium, we used information from the literatureto assign them to a GO term. For some of thegenes designated “unknown function” by GO, wewere able to assign provisional functions on thebasis of published literature (see appendix), butthese genes are included in the “unknown func-tion” category of this figure. As indicated by theboxed legend, each bar indicates classification ofthe human MR genes based on the degree ofsimilarity to Drosophila genes.

systems-level perspectives (Figure 4; appendix; see ma- The major signaling pathways are represented amongthe MR genes, including those regulated by Sonicterials and methods). The basic cellular processes con-

trolled by MR genes take place in the nucleus, in the Hedgehog (e.g., SHH), the TGF-� family of growth fac-tors (e.g., GPC3), Notch (e.g., JAG1), and calcium (e.g.,cytoplasm (including within organelles), and at the in-

terface among cells, cell compartments, and the extra- ATP2A2). MR-related signaling cascades are mediatedby diverse cell surface proteins, such as integrins (e.g.,cellular milieu. In the nucleus, MR genes affect chromo-

some structure (e.g., DNMT3B), DNA repair (e.g., NBS1), ITGA7), G protein-coupled receptors (e.g., AGTR2), re-ceptor tyrosine kinases (e.g., NTRK1), and intracellularbasal and regulated transcription (e.g., ERCC2 and SIX3,

respectively), as well as rRNA processing (e.g., DKC1). proteins, including small G proteins (e.g., GDI1), hetero-trimeric G proteins (e.g., GNAS), and phosphatidylinosi-In the cytoplasm, many MR genes have metabolic

functions (see also Kahler and Fahey 2003), involving tol (e.g., PTEN). Moreover, genes in a common pathwaycan share MR as a phenotype. SHH (Ming et al. 1998),a wide range of pathways [citric acid cycle (e.g., FH),

gluconeogenesis (e.g., GK), glycolysis (e.g., PDHA1), oxi- through its receptors encoded by PTCH and PTCH2,regulates GLI3, some of whose targets are also regulateddation (e.g., the PEX genes), oxidative phosphorylation

(e.g., MTCO1), urea cycle (e.g., OTC), and general cell by GPC3.MR genes also control communication and transportintegrity (e.g., GSS)] and biologically critical com-

pounds [amine (e.g., MAOA), amino acid (e.g., OAT), across cell and organelle membranes. These includecation-chloride cotransporters (SLC12A1, SLC12A6)carbohydrate (e.g., GALE), cholesterol (e.g., SC5DL),

creatine (e.g., GATM), fatty acid (e.g., ALDH3A2), heme that may be critical for inhibitory neurotransmission(Payne et al. 2003). The transmembrane linkage (ITGA7,(e.g., PPOX), lipid (e.g., DIA), methionine (e.g.,

MAT1A), purine (e.g., HPRT), pyrimidine (e.g., DPYD), TM4SF2) between the extracellular matrix (LAMA2) andthe cytoskeleton is strongly implicated in MR, as is celland cofactors (e.g., TC2)]. MR genes involved in macro-

molecular synthesis and modification include those re- adhesion (L1CAM).The overlap between MR and muscle disease is strik-quired for mitochondrial translation (e.g., MTTK),

translation regulation (e.g., FMR1), protein folding (e.g., ing and appears to arise from at least three distinctmechanisms: reduced membrane/cytoskeletal stabilityBBS6), protein stability (e.g., PPGB), protein glycosyla-

tion (e.g., PPM2), and lipid synthesis (FACL4). Macro- (DMD, ITGA7, LAMA2); glycosylation defects associatedwith abnormal neuronal migration (FCMD, FKRP,molecular degradation in lysosomal (e.g., HEXA) and

proteasomal (e.g., UBE3A) pathways is also commonly LARGE, POMGNT1, POMT1); and mitochondrial dys-function (MTCO3 and many others). The biologicaldisrupted by mutations in MR genes. MR genes have

major effects on the cytoskeleton, including its actin basis of myotonic dystrophy (DM1) is unknown.An integrative view of MR biology: The hereditary(e.g., FLNA), microtubule (e.g., DCX), and intermediate

filament (e.g., GFAP) components. MR disorders can be approached from two somewhat


Figure 4.—Biological functions that underliemental retardation. Diagram of a mammalian cor-tical neuron and associated structures in the cen-tral nervous system. The physiological connectionto the endocrine system via the bloodstream isindicated in the bottom left. Sizes are not to scale.Solid triangles represent hormone molecules.Each of the unboxed terms, in roman type, is abiological function regulated by one or more MRgenes or results from mutation of an MR gene(see appendix).

independent perspectives: (i) where the genes are ex- pancreas to regulate ATP-dependent, exocytotic insulinsecretion. Mutations in either gene cause excess insu-pressed and function and (ii) the relationship between

the mutation and pathogenesis of the MR phenotype. lin release and hypoglycemia which, if inadequatelytreated, disrupts brain development and function dueGenes may act selectively within the brain (“intrinsic

or selective function”) or primarily outside the CNS to systemic fuel deficiency (Vannucci and Vannucci2001; Huopio et al. 2002). Similarly, the brain’s energy(“extrinsic or generalized function”). MR may result

from fundamental cellular defects that impair many requirements make it very sensitive to genetic disrup-tions of mitochondrial function (Chow and Thorburntissues (“generic effect”), with the brain sometimes hav-

ing a higher sensitivity, or MR can result from selective 2000). Mutations in mitochondrial genes (MTATP6,MTCO1, MTCO2, MTCO3, MTCYB, MTTE, MTTK,impairment of unique features of brain development

or physiology (“selective effect”). With the caveat that MTTL1, MTTS1) or in nuclear genes encoding mito-chondrial proteins (BCS1L, SCO2, SURF1, TIMM8A)MR pathogenesis is incompletely understood and that

spatial expression data are limited, we consider exam- cause MR due to local energy (ATP) deficiency in neu-rons and glia (Servidei 2001).ples of MR genes in these major categories.

Extrinsic or generalized function/generic effect: ABCC8 Extrinsic or generalized function/selective effect: In the en-docrine system, locally synthesized hormones enter the(SUR1) and KCNJ11 gene products work together in the


circulation and affect distant organs. MR genes include aly (“smooth brain”) due to mutations in LIS1, DCX,and RELN, as well as ARX (some alleles) and FLNAseveral tissue-specific regulators of thyroid gland devel-

opment (TTF2, PAX8) or thyroid hormone synthesis (Olson and Walsh 2002). Agenesis (partial or com-plete) and dysgenesis of the interhemispheric corpus(DUOX2, TG, TPO ; Kopp 2002). Mutations in these

cause congenital hypothyroidism, and mutations in a callosum (Davila-Gutierrez 2002) are relatively com-mon MR-associated phenotypes (e.g., CXORF5, GLI3,receptor (THRB) cause thyroid hormone resistance. In

either case, brain cells cannot initiate the transcriptional OCRL, SLC12A6, TSC1, TSC2) and may be isolated oraccompany holoprosencephaly and other abnormali-cascade that controls neuronal size, migration, and den-

dritic morphology, as well as oligodendrocyte differenti- ties.A handful of MR genes and their primary cellularation (Thompson and Potter 2000). Hence, neuronal

circuitry and myelination are disrupted. phenotypes are glia specific. Dominant missense muta-tions in GFAP cause Alexander disease due to astrocyticMany metabolic MR genes fall into this category as

well. AASS is expressed in most tissues and encodes a accumulation of abnormal intermediate filaments andsecondary demyelination (Johnson 2002). In contrast,key enzyme in lysine metabolism (Sacksteder et al.

2000). In patients lacking AASS function, lysine accumu- PLP1 is expressed solely in oligodendrocytes and en-codes the most abundant CNS myelin protein. Myelinlates and inhibits arginase, causing excess circulating

ammonia, which interferes with neuronal and glial func- integrity is very sensitive to PLP1 gene dosage, with du-plications, deletions, and missense mutations all caus-tions (Felipo and Butterworth 2002). Similarly, PAH

is expressed mainly in nonneural tissues (Lichter- ing Pelizaeus-Merzbacher disease (Koeppen and Robi-taille 2002).Konecki et al. 1999), with mutations causing elevated

circulating phenylalanine. This systemic toxin impairs At the other end of the spectrum are the many heredi-tary MR disorders for which routine neuropathologicalmyelination, synaptogenesis (Bauman and Kemper

1982; Huttenlocher 2000), and possibly aminergic data are unavailable or fail to show consistent defects.Higher-resolution Golgi staining has revealed dendriticneurotransmission (Surtees and Blau 2000). The lyso-

somal storage disorders, which cause macromolecules abnormalities of cortical neurons in fragile-X (FMR1;Irwin et al. 2000) and Rett syndromes (MECP2; Arm-to accumulate in many tissues, may also belong to this

category. Most represent degradative enzyme deficien- strong 2001) and possibly in Rubinstein-Taybi syn-drome (CREBBP ; Kaufmann and Moser 2000). Allcies, but some of the genes encode transport, stabilizer,

or activator proteins (Wisniewski et al. 2001). They are three likely result from misregulated gene expressionin the brain, but which target genes are responsible forclassified by the compounds that accumulate in lyso-

somes, such as sphingolipidoses (e.g., ARSA), neuronal the dendritic defects remain to be determined.For MR disorders with no known anatomical lesions,ceroid lipofuscinoses (e.g., CLN1), glyoproteinoses (e.g.,

PPGB), and mucolipidoses (e.g., NEU1). The traditional such as nonsyndromal MRX, gene function in the CNSis inferred from molecular analyses. For example, GDI1view that the progressive brain phenotypes result “sim-

ply” from local toxicity is countered by reports of specific (MRX41, MRX48; Bienvenu et al. 1998) encodes abrain-specific regulator of Rab-type G proteins. One ofneurodevelopmental defects (Walkley 1998; Alta-

rescu et al. 2002). its targets is believed to be Rab3A, which controls activ-ity-dependent synaptic vesicle recruitment to axon ter-Intrinsic function/selective effect: For genes with selective

expression or function within the CNS, the conse- minals (Leenders et al. 2001). Given the structure-func-tion relationships underlying developmental synapticquences of mutations are also primarily CNS selective,

with variation in cell-type involvement and severity plasticity (Cohen-Cory 2002), it seems likely that neuro-anatomical phenotypes for this and other MRX disor-(Pomeroy and Kim 2000). The coexistence of neuro-

pathology and cognitive deficits supports the view of ders will eventually be found.Regardless of the scheme used, many disorders defyMR as a disorder of brain development or plasticity. At

one end of the spectrum are MR disorders with gross straightforward classification. For example, the role ofhomocysteine in CNS development and functionbrain malformations. Holoprosencephaly, a failure of

the right and left brain halves to form distinct hemi- (Mattson and Shea 2003) belies the “metabolic” classi-fication of the MR genes CBS, MTHFR, MTR, MTRR,spheres, results from mutations in genes controlling

cellular identity of forebrain neuronal precursors and TC2. The MR genes SC5DL and DHCR7 encodeenzymes in cholesterol biosynthesis, making them also(PTCH, SHH, SIX3, TDGF1, TGIF, ZIC2; Wallis and

Muenke 2000). Schizencephaly (“cleft brain”) is due to primarily “metabolic.” However, because Sonic Hedge-hog protein function is absolutely dependent on cova-dominant missense mutations in EMX2, which encodes

a homeodomain-containing transcription factor (Faiella lent linkage to cholesterol (Ingham and McMahon2001), the enzymatic deficiencies may impair SHH sig-et al. 1997). Abnormal neuronal migration in the rostral

forebrain (the region of EMX2 expression) causes gross naling. It may be that, with sufficient research on molec-ular and cellular pathogenesis, few if any MR genes willmorphogenetic as well as more subtle lamination de-

fects. Neuronal migration defects also cause lissenceph- be considered “just metabolic.”


TA

BL

E3

Hum

anm

enta

lre

tard

atio

nge

nes:

prim

eca

ndid

ates

for

stud

yin

D.

mel

anog

aste

r

Dro

soph

ilaor

thol

og

Mam

mal

ian

brai

nM

ouse

Gen

eH

uman

gen

eaH

uman

dise

aseb

phen

otyp

ein

clud

es:c

mut

ant/

MR

dG

ene

nam

eelo

cati

onM

utan

tsB

iolo

gica

lfu

nct

ion

inD

roso

phila

f

AR

HG

EF6

(1)

MR

X46

Pres

umed

toh

ave

no

Non

ert

GEF

38C

NP

[Rh

opa

thw

ay;

acti

ncy

tosk

elet

on;

obvi

ous

defe

cts

mor

phog

enes

is]

ASP

M(2

)Pr

imar

ym

icro

ceph

aly

5M

icro

ceph

aly

Non

eab

norm

alsp

indl

e96

AYe

s,N

Spin

dle

form

atio

n;

cyto

kin

esis

AT

P2A

2(3

)D

arie

r-W

hit

edi

seas

eU

nkn

own

Yes/

?C

alci

umA

TPa

se60

AYe

sPr

otei

ntr

affi

ckin

g/po

st-tr

ansl

atio

nal

60A

proc

essi

ng

AT

RX

(4)

�-T

hal

asse

mia

/MR

syn

drom

e;M

ildce

rebr

alat

roph

y;N

one

XN

P96

EU

P[T

ran

scri

ptio

nre

gula

tion

;ch

rom

atin

non

spec

ific

MR

mic

roce

phal

y;A

CC

stru

ctur

e]C

REB

BP

(5)

Rub

inst

ein

-Tay

bisy

ndr

ome

AC

C;

decr

ease

dde

ndr

itic

Yes/

yes

nejir

e9A

Yes,

NT

GF-

�/W

nt

sign

alin

g;N

MJ

arbo

riza

tion

stru

ctur

e/fu

nct

ion

DC

X(6

)X

-lin

ked

lisse

nce

phal

yA

bnor

mal

cort

ical

lam

inat

ion

:Ye

s/ye

sC

G17

528

41A

CN

one

[Mic

rotu

bule

cyto

skel

eton

;n

euri

teh

eter

otop

ia,

pach

ygyr

iaou

tgro

wth

]D

KC

1(7

)D

yske

rato

sis

con

gen

ita;

HH

SA

CC

;ce

rebe

llar

hyp

opla

sia;

Yes/

?N

ucle

olar

prot

ein

60C

Yes

rRN

Apr

oces

sin

g;ce

llan

dor

gan

ism

alsl

owm

yelin

atio

n60

Bgr

owth

DM

D(8

)D

uch

enn

e/B

ecke

rm

.N

euro

nlo

ss;

abn

orm

alYe

s/ye

sdy

stro

phin

92A

NP

[Pla

sma

mem

bran

e-cy

tosk

elet

ondy

stro

phy

den

drit

es;

astr

ocyt

osis

linka

ge]

FGFR

-1,-2

,A

pert

and

oth

erA

CC

;ab

nor

mal

limbi

can

dYe

s/?

brea

thle

ss70

CYe

s,N

Glia

lce

llm

igra

tion

-3(9

)cr

anio

syn

osto

sis

syn

drom

espy

ram

idal

trac

t;h

eter

otop

iaYe

s/?

hear

tless

90E

Yes,

NA

xon

outg

row

th,

guid

ance

,an

dw

rapp

ing

bygl

iaFL

NA

(10)

Peri

ven

tric

ular

nod

ular

Peri

ven

tric

ular

het

erot

opia

;N

one

chee

rio

89E

Yes,

NA

ctin

fila

men

tor

gan

izat

ion

;h

eter

otop

iaA

CC

;ce

rebe

llar

hyp

opla

sia

lon

g-te

rmm

emor

yFM

R1

(11)

Frag

ileX

men

tal

reta

rdat

ion

Abn

orm

alde

ndr

itic

spin

es,

Yes/

yes

dfm

r185

FYe

s,N

Tra

nsl

atio

nre

gula

tion

;n

euro

nsy

ndr

ome

?im

mat

ure

stru

ctur

e/fu

nct

ion

FOX

P2(1

2)D

evel

opm

enta

lve

rbal

Abn

orm

alfr

onta

llo

bem

otor

Non

eC

G16

899

85E

NP

[Tra

nsc

ript

ion

regu

lati

on]

dysp

raxi

aar

eas

GD

I1(1

3)M

RX

41,

MR

X48

No

obvi

ous

defe

cts

Yes/

yes

GD

I30

BYe

sR

abG

TPa

sebi

ndi

ng;

grow

th;

pupa

riat

ion

GL

I3(1

4)A

croc

allo

sal

syn

drom

e;A

CC

;↓n

eura

ltu

beap

opto

sis;

Yes/

?cu

bitu

sin

terr

uptu

s10

2AYe

s,N

Hh

path

way

;tr

ansc

ript

ion

;n

euro

not

her

sab

nor

mal

DV

patt

ern

diff

eren

tiat

ion

GN

AS

(15)

Alb

righ

th

ered

itar

yC

ereb

ral

calc

ifica

tion

Yes/

?G

prot

ein

s�60

A60

AYe

s,N

Loc

omot

orbe

hav

ior;

lear

nin

g;os

teod

ystr

oph

yph

otot

ran

sduc

tion

GPC

3(1

6)Si

mps

on-G

olab

i-Beh

mel

Un

know

nYe

s/?

dally

66E

Yes,

NW

ntp

ath

way

;cel

lcyc

le;n

euro

gen

esis

syn

drom

ety

peI

GPH

(17)

Mol

ybde

num

cofa

ctor

Cer

ebra

lat

roph

y;↓G

lyR

and

Yes/

yes

cinn

amon

1AYe

sM

olyb

den

umco

fact

orbi

osyn

thes

isde

fici

ency

type

CG

AB

A-R

clus

teri

ng

GPI

(18)

Hem

olyt

ican

emia

?Los

sof

neu

rotr

oph

icac

tivi

tyYe

s/?

pgi

44F

Yes

Glu

cose

met

abol

ism

;[n

euro

nal

surv

ival

]IT

GA

7(1

9)C

onge

nit

alm

yopa

thy

Cor

tica

lat

roph

y;ab

nor

mal

Non

em

ew11

EYe

s,N

Tis

sue

adh

esio

n;c

ellm

igra

tion

;axo

nw

hit

em

atte

rpa

thfi

ndi

ng

(con

tinue

d)


TA

BL

E3

(Con

tinu

ed)

Dro

soph

ilaor

thol

og

Mam

mal

ian

brai

nM

ouse

Gen

eH

uman

gen

eaH

uman

dise

aseb

phen

otyp

ein

clud

es:c

mut

ant/

MR

dG

ene

nam

eelo

cati

onM

utan

tsB

iolo

gica

lfu

nct

ion

inD

roso

phila

f

JAG

1(2

0)A

lagi

llesy

ndr

ome

Abn

orm

alve

ssel

s(m

oyam

oya)

Yes/

?Se

rrat

e97

EYe

s,N

Not

chpa

thw

ay;

cell

fate

;an

dn

euro

nal

patt

ern

ing

neu

roge

nes

isL

1CA

M(2

1)M

ASA

syn

drom

e;H

SAS;

AC

C;

hyd

roce

phal

usYe

s/ye

sne

urog

lian

7FYe

s,N

Neu

ron

adh

esio

n/m

orph

olog

y;ax

onSP

G1

path

fin

din

gL

AM

A2

(22)

Con

gen

ital

mus

cula

rA

bnor

mal

lam

inat

ion

and

Yes/

yes

win

gbl

iste

r35

AYe

sC

ell

mig

rati

onan

dad

hes

ion

dyst

roph

yw

hit

em

atte

r;↓c

ereb

ellu

mL

IS1

(23)

Lis

sen

ceph

aly;

↓Cor

tica

lla

min

atio

n:

Yes/

yes

Lis

senc

epha

ly-1

52F

Yes,

NN

euro

gen

esis

;de

ndr

itog

enes

is;

peri

ven

tric

ular

pach

y/ag

yria

,h

eter

otop

iaax

onal

tran

spor

th

eter

otop

iaM

ID1

(24)

Opi

tzsy

ndr

ome

type

IA

CC

and

oth

erm

idlin

eN

one

CG

3172

132

AN

P?E

mbr

yon

icC

NS

deve

lopm

ent

defe

cts;

cort

ical

atro

phy

(CG

6256

)M

YO5A

(25)

Ele

jald

esy

ndr

ome

Cer

ebel

lar

hyp

opla

sia;

Yes/

yes

didu

m43

DU

PE

mbr

yoge

nes

isab

nor

mal

den

drit

icsp

ines

NF1

(26)

Neu

rofi

brom

atos

isM

egen

ceph

aly;

abn

orm

alYe

s/ye

sN

euro

fibro

min

196

FYe

s,N

Ras

path

way

;gl

ial

grow

th;

lear

nin

g/w

hit

em

atte

r;gl

ial

tum

ors

mem

ory

NSD

1(2

7)N

ijmeg

enbr

eaka

geA

CC

;po

lygy

ria;

dila

ted

Non

eM

es-4

98B

NP

[Tra

nsc

ript

ion

regu

lati

on]

syn

drom

eve

ntr

icle

sO

CR

L(2

8)L

owe

ocul

ocer

ebro

ren

alA

CC

;ab

nor

mal

wh

ite

mat

ter

Yes/

no

EG:8

6E4.

52B

NP

[In

osit

olph

osph

ate

path

way

;sy

ndr

ome

?pro

tein

sort

ing]

OPH

N1

(29)

MR

X60

Pres

umed

toh

ave

no

obvi

ous

Non

eG

raf

13E

NP;

R;

NA

xon

stab

ility

defe

cts

PAK

3(3

0)M

RX

30;

MR

X47

No

obvi

ous

defe

cts

Non

ePa

k83

EYe

s,N

Axo

npa

thfi

ndi

ng

PRSS

12(3

1)A

utos

omal

rece

ssiv

ePr

esum

edto

hav

en

oob

viou

sN

one

Teq

uila

66F

NP

[Ser

ine

prot

ease

]n

onsp

ecifi

cM

Rde

fect

sPT

EN(3

2)C

owde

nsy

ndr

ome;

Meg

ence

phal

y;ab

nor

mal

Yes/

yes

Pten

31B

Yes

Cel

lsi

zean

dpr

olif

erat

ion

;in

sulin

Ban

nay

an-Z

onan

ala

min

atio

n;↑n

euro

nsi

zepa

thw

aysy

ndr

ome

PTPN

11(3

3)N

oon

ansy

ndr

ome;

Un

know

nYe

s/?

cork

scre

w2D

Yes,

NR

TK

path

way

s;ce

llfa

te,

mig

rati

on,

LE

OPA

RD

syn

drom

epa

thfi

ndi

ng

RSK

2(3

4)C

offi

n-L

owry

syn

drom

e;A

CC

;di

late

dve

ntr

icle

sYe

s/ye

sS6

kII

20A

Yes,

N[S

ign

alin

gpa

thw

ays]

;le

arn

ing

and

MR

X19

mem

ory

SHH

(35)

Hol

opro

sen

ceph

aly

3H

olop

rose

nce

phal

y;ve

ntr

alYe

s/ye

she

dgeh

og94

EYe

s,N

Mor

phog

enex

pres

sion

;pa

tter

nin

g;fa

tefa

ilure

neu

roge

nes

isSI

X3

(36)

Hol

opro

sen

ceph

aly

2H

olop

rose

nce

phal

yN

one

Opt

ix44

AN

PIn

duce

sey

ede

velo

pmen

tSO

X3

(37)

MR

wit

hgr

owth

hor

mon

eU

nkn

own

Non

eSo

xNeu

ro29

FYe

s,N

Cel

lfa

te;

neu

roge

nes

is;

axon

defi

cien

cygu

idan

ceT

BC

E(3

8)H

RD

syn

drom

eU

nkn

own

;?ax

onde

gen

erat

ion

Yes/

yes

CG

7861

42A

UP

[Ch

aper

one;

tubu

linfo

ldin

gan

d(s

eeap

pen

dix

)di

mer

izat

ion

]

(con

tinue

d)


TA

BL

E3

(Con

tinu

ed)

Dro

soph

ilaor

thol

og

Mam

mal

ian

brai

nM

ouse

Gen

eH

uman

gen

eaH

uman

dise

aseb

phen

otyp

ein

clud

es:c

mut

ant/

MR

dG

ene

nam

eelo

cati

onM

utan

tsB

iolo

gica

lfu

nct

ion

inD

roso

phila

f

TSC

2(3

9)T

uber

ous

scle

rosi

s2

Cor

tica

ltu

bers

;su

bcor

tica

lYe

s/ye

sgi

gas

76F

Yes,

NC

ells

ize;

cell

cycl

e;ax

onpa

thfi

ndi

ng

nod

ules

;as

troc

ytom

asU

BE3

A(4

0)A

nge

lman

syn

drom

e“A

trop

hy”

;ab

nor

mal

gyra

lYe

s/ye

sC

G61

9068

BU

P[S

elec

tive

prot

ein

degr

adat

ion

]pa

tter

n;↓d

endr

itic

arbo

rsZI

C2

(41)

Hol

opro

sen

ceph

aly

5H

olop

rose

nce

phal

y;de

fect

ive

Yes/

yes

odd

pair

ed82

EYe

sT

issu

em

orph

ogen

esis

;n

euru

lati

on[i

nte

ract

sw

ith

Hh

path

way

]

AC

C,a

gen

esis

,dys

gen

esis

,or

hyp

opla

sia

ofth

eco

rpus

callo

sum

;DV

,dor

sal-v

entr

al;U

P,un

char

acte

rize

dP

-ele

men

tin

sert

ion

inth

ege

ne;

NP,

nea

rby

Pel

emen

ts;N

one,

no

mut

ants

and

no

Pel

emen

tskn

own

tobe

nea

rby;

R,

fun

ctio

nas

sess

edby

doub

le-s

tran

ded

RN

Ain

terf

eren

ce;

N,

beh

avio

ral

and/

orn

euro

anat

omic

alph

enot

ype

resu

lts

from

disr

upti

onby

mut

atio

nor

RN

Ai;

Hh

,h

edge

hog

;N

MJ,

neu

rom

uscu

lar

jun

ctio

n;

RT

K,

rece

ptor

tyro

sin

eki

nas

e.?,

prec

edes

phen

otyp

essu

gges

ted

but

not

con

clus

ivel

yde

mon

stra

ted.

aSe

eap

pen

dix

for

alte

rnat

ege

ne

sym

bols

.N

umbe

rsin

pare

nth

eses

follo

win

gin

divi

dual

gen

esre

fer

tore

pres

enta

tive

refe

ren

ces

from

the

mam

mal

ian

and

Dro

soph

ilage

net

ics

liter

atur

e:(1

)K

uts

che

etal

.(20

00);

Wer

ner

and

Man

seau

(199

7);(

2)B

on

det

al.(

2002

);W

akefi

eld

etal

.(20

01);

(3)

Jaco

bsen

etal

.(19

99);

Peri

zan

dFo

rtin

i(1

999)

;(4)

Gib

bon

san

dH

igg

s(2

000)

;(5)

Can

tan

ian

dG

agli

esi

(199

8);N

ewfe

ldan

dT

akae

su(2

002)

;Mar

eket

al.(

2000

);(6

)Fr

ioco

urt

etal

.(20

03);

(7)

Aka

bosh

iet

al.

(200

0);

Gio

rdan

oet

al.

(199

9);

(8)

An

der

son

etal

.(2

002)

;G

reen

eran

dR

obe

rts

(200

0);

(9)

Pass

os-

Bu

eno

etal

.(1

999)

;K

lam

btet

al.

(199

2);

Gar

cia-

Alo

nso

etal

.(2

000)

;Sh

ish

ido

etal

.(1

997)

;(1

0)Fo

xet

al.

(199

8);

Li

etal

.(1

999)

;D

ubn

auet

al.

(200

3);

(11)

Irw

inet

al.

(200

0);

Zh

ang

etal

.(2

001)

;D

ock

end

orf

fet

al.

(200

2);

Ish

izu

kaet

al.

(200

2);

Mo

rale

set

al.

(200

2);

C.

Mic

hel

,R

.K

raft

,B

.H

assa

nan

dL

.R

esti

fo(u

npu

blis

hed

resu

lts)

;(1

2)V

arg

ha-

Kh

adem

etal

.(1

998)

;(1

3)B

ien

ven

uet

al.

(199

8);

Ric

ard

etal

.(2

001)

;(1

4)E

lso

net

al.

(200

2);

Hu

ang

and

Ku

nes

(199

8);

(15)

Ald

red

and

Tre

mba

th(2

000)

;C

on

no

lly

etal

.(1

996)

;C

hyb

etal

.(1

999)

;W

olf

gan

get

al.

(200

1);(

16)

Li

etal

.(2

001)

;Nak

ato

etal

.(1

995)

;T

sud

aet

al.

(199

9);

(17)

Rei

sset

al.(

2001

);W

ittl

eet

al.

(199

9);(

18)

Lu

oet

al.

(200

2);K

ug

ler

and

Lak

om

ek(2

000)

;see

FlyB

ase

IDFB

gn00

0307

4;(1

9)B

oke

lan

dB

row

n(2

002)

;Peg

ora

roet

al.(

2002

);H

oan

gan

dC

hib

a(1

998)

;(20

)W

oo

lfen

den

etal

.(19

99);

Kra

ntz

etal

.(1

998)

;T

sai

etal

.(2

001)

;G

uet

al.

(199

5);

Flem

ing

etal

.(1

990)

;(2

1)W

elle

ran

dG

artn

er(2

001)

;G

arci

a-A

lon

soet

al.

(200

0);

Hal

lan

dB

iebe

r(1

997)

;(2

2)Jo

nes

etal

.(2

001)

;M

arti

net

al.

(199

9);

(23)

Car

do

soet

al.

(200

2);

Liu

etal

.(2

000)

;(2

4)C

ox

etal

.(2

000)

;B

rod

yet

al.

(200

2);

(25)

San

alet

al.

(200

0);

Tak

agis

hi

etal

.(19

96);

Mac

Iver

etal

.(19

98);

(26)

Lyn

chan

dG

utm

ann

(200

2);Y

ager

etal

.(20

01);

Gu

oet

al.(

2000

);(2

7)D

ou

gla

set

al.(

2003

);(2

8)L

inet

al.(

1998

);(2

9)B

illu

art

etal

.(1

998,

2001

);(3

0)B

ien

ven

uet

al.

(200

0);A

llen

etal

.(1

998)

;H

ing

etal

.(1

999)

;(3

1)M

oli

nar

iet

al.

(200

2);

(32)

Mar

shet

al.

(199

8);

Li

etal

.(2

003)

;O

ldh

amet

al.

(200

2);(

33)

Mu

san

teet

al.

(200

3);P

erki

ns

etal

.(1

996)

;(34

)Ja

cqu

ot

etal

.(2

002)

;G.P

utz

,T.Z

ars

and

M.H

eise

nbe

rg(p

erso

nal

com

mun

icat

ion

);(3

5)O

den

tet

al.

(199

9);

Ing

ham

and

McM

aho

n(2

001)

;(3

6)Pa

squ

ier

etal

.(2

000)

;Se

imiy

aan

dG

ehri

ng

(200

0);

(37)

Lau

mo

nn

ier

etal

.(2

002)

;B

ues

cher

etal

.(2

002)

;O

vert

on

etal

.(2

002)

;(38

)Pa

rvar

iet

al.

(200

2);M

arti

net

al.(

2002

);(3

9)M

izu

gu

chi

and

Tak

ash

ima

(200

1);T

apo

net

al.(

2001

);C

anal

etal

.(1

998)

;(40

)C

layt

on

-Sm

ith

and

Laa

n(2

003)

;(4

1)B

row

net

al.

(200

1);

Nag

aiet

al.

(200

0);

Cim

bora

and

Sako

nju

(199

5).

bA

ddit

ion

aldi

sord

ers

may

beca

used

bym

utat

ion

ofth

ese

gen

es;

see

the

appe

nd

ix.

cB

ased

onn

euro

path

olog

y,n

euro

phys

iolo

gy,

and/

orbr

ain

imag

ing

ofh

uman

pati

ents

.In

som

eca

ses,

data

from

mou

sem

utan

tsw

ere

also

con

side

red.

dYe

s/ye

s,m

ouse

mut

ant

disp

lays

an

euro

logi

cal

orbe

hav

iora

lph

enot

ype

rele

van

tto

MR

;ye

s/?,

mou

sem

utan

th

asn

otye

tbe

ench

arac

teri

zed

neu

rolo

gica

lly;

yes/

no,

mou

sem

utan

th

asn

okn

own

neu

rolo

gica

lph

enot

ype;

non

e,n

om

ouse

mut

ant.

eT

he

Dro

soph

ilage

nes

wit

hpr

efixe

s“C

G”

and

“EG

”h

ave

been

iden

tifi

edon

lyby

gen

ome

sequ

enci

ng

proj

ects

(see

FlyB

ase

ath

ttp:

//fl

ybas

e.bi

o.in

dian

a.ed

u/fo

rde

tails

).Se

eap

pen

dix

for

BL

AST

PE-

valu

es.

fB

iolo

gica

lfu

nct

ion

sin

brac

kets

are

infe

rred

from

mol

ecul

arda

ta(i

ncl

udin

gge

ne

expr

essi

onan

dbi

och

emis

try)

orse

quen

ceh

omol

ogy

topr

otei

ns

ofkn

own

fun

ctio

n.

All

oth

ers

are

base

don

mut

ant

phen

otyp

es.


The role of D. melanogaster in MR research: In terms a ligand of Notch (the Drosophila ligand is Serrate).The biological relevance of genetic interactions in hu-of primary amino acid sequence and protein-domain orga-

nization, the degree of MR gene conservation between man MR is well demonstrated by some of the Bardet-Biedl syndromes (BBS2 and BBS6; see appendix) inhumans and Drosophila is remarkable (Figure 1; appen-

dix). Not only individual genes but also whole pathways which clinical manifestations result from “triallelic in-heritance,” homozygosity at one locus and heterozygos-have been retained through �700 million years of evolu-

tion. These include protein glycosylation (ALG3, ALG6, ity at another (Katsanis et al. 2001). Genetic interactiontests in Drosophila could help clarify the functionalB4GALT1, DPM1, FUCT1, GCS1, MGAT2, MPDU1, PMI,

PPM2), as well as signaling pathways, notably the Hedge- relevance of the physical interaction between mamma-lian ZIC2 and GLI3 proteins (Koyabu et al. 2001).hog pathway (SHH, PTCH, PTCH2, GLI3, GPC3) and those

mediated by small G proteins (ARHGEF6, GDI1, OPHN1, The number of MR genes is very large, but they may beinvolved in a relatively small number of interconnectedPAK3, FGD1, GPH, RSK2, and others).

Given this remarkable conservation of MR genes, we pathways. If so, a modest number of pharmacologicaltreatment strategies might be effective for many MRpropose that Drosophila genetics can be used in a sys-

tematic manner to study MR. We have selected 42 fly patients. In fact, some types of acquired MR might bene-fit from the same drugs. Diagnoses of hereditary MR aregenes (the orthologs of 43 human MR genes) as “prime

candidates” for such analyses (Table 3). These genes typically made early in life at a time when developmentalbrain plasticity provides an opportunity for therapeuticmost likely act selectively within the brain during devel-

opment to establish the anatomical and physiological intervention. The widespread functional conservationof MR genes in Drosophila indicates that this geneticsubstrates for experience-dependent plasticity. The ma-

jority of prime-candidate orthologs currently have fly model system could play a critical role in the discoveryof novel treatment strategies for MR.mutants available (about the same fraction as have

mouse mutants available) and the rest can be mutagen- The authors thank Brian Blood for recent literature searches andized through the mobilization of nearby transposable BLAST analyses to update the list of human MR genes and their

Drosophila homologs. The authors are grateful to colleagues Davidelements or studied using RNA interference methodsMount for advice on bioinformatics methods, Terrill Yuhas and Nirav(Adams and Sekelsky 2002). About half are alreadyMerchant for computer support, Charles Hedgecock for assistanceknown to have neural phenotypes, behavioral or ana-with computer graphics, and John Meaney and Robert Erickson for

tomical, in Drosophila (Table 3 and references therein). helpful discussions about human genetic disease. This work wasThe anatomical defects involve neurons (e.g., cubitus funded by the National Institutes of Health (grant no. P01 NS028495).interruptus), glia (e.g., Neurofibromin 1), and neural pre-

Note added in proof: Evaluation of recently updated OMIM entriescursor cells (e.g., division abnormally delayed) and resultrevealed three more MR genes whose molecular identifications werefrom problems with proliferation (e.g., hedgehog), migra-published prior to September 30, 2003. They are AAAS (OMIM

tion (e.g., breathless), and process extension or arboriza- 605378), COH1 (OMIM 607817), and MLC1 (OMIM 605908).tion (e.g., Pak, dfmr1). For a few genes, neuronal defectsin the mushroom bodies, an arthropod learning andmemory center (Zars 2000), have been demonstrated LITERATURE CITED(e.g., Lissencephaly 1; Drosophila fragile-X mental retarda-

Adams, M. D., and J. J. Sekelsky, 2002 From sequence to phenotype:tion 1). reverse genetics in Drosophila melanogaster. Nat. Rev. Genet. 3:

189–198.How will the Drosophila developmental neurogene-Adams, M. D., S. E. Celniker, R. A. Holt, C. A. Evans, J. D. Gocaynetics system contribute to the understanding and treat-

et al., 2000 The genome sequence of Drosophila melanogaster.ment of these challenging human disorders? First, cellu- Science 287: 2185–2195.

Aicardi, J., 1998 The etiology of developmental delay. Semin. Pedi-lar phenotypes, including those detected in primaryatr. Neurol. 5: 15–20.neuronal culture (Kraft et al. 1998; R. Kraft, J. Kurtis

Akaboshi, S., M. Yoshimura, T. Hara, H. Kageyama, K. Nishikwaand L. Restifo, unpublished results), could provide et al., 2000 A case of Hoyeraal-Hreidarsson syndrome: delayed

myelination and hypoplasia of corpus callosum are other impor-bioassays for drug testing. Second, genetic interactiontant signs. Neuropediatrics 31: 141–144.studies will likely identify novel MR genes, as well as

Aldred, M. A., and R. C. Trembath, 2000 Activating and inactivat-reveal the interconnected structure of MR gene path- ing mutations in the human GNAS1 gene. Hum. Mutat. 16: 183–

189.ways.Allen, K. M., J. G. Gleeson, S. Bagrodia, M. W. Partington, J.The degree to which fly mutant phenotypes “match”

C. MacMillan et al., 1998 PAK3 mutation in nonsyndromicthose of human patients remains to be seen, but it may X-linked mental retardation. Nat. Genet. 20: 25–30.

Altarescu, G., M. Sun, D. F. Moore, J. A. Smith, E. A. Wiggs et al.,not matter nearly as much as the genetic pathways in-2002 The neurogenetics of mucolipidosis type IV. Neurologyvolved, as these are likely to guide targeted drug discov-59: 306–313.

ery. For example, the fly ortholog of the MR gene Altschul, S. F., T. L. Madden, A. A. Schaffer, J. Zhang, Z. Zhanget al., 1997 Gapped BLAST and PSI-BLAST: a new generationATP2A2 was identified in a screen for enhancers ofof protein database search programs. Nucleic Acids Res. 25: 3389–Notch (Periz and Fortini 1999). The role of the Notch3402.

pathway in MR is revealed by Alagille syndrome due to Anderson, J. L., S. I. Head, C. Rae and J. W. Morley, 2002 Brainfunction in Duchenne muscular dystrophy. Brain 125: 4–13.mutations in JAG1 (Krantz et al. 1998), which encodes


Apweiler, R., T. K. Attwood, A. Bairoch, A. Bateman, E. Birney 1999 Modulation of the light response by cAMP in Drosophilaet al., 2001 The InterPro database, an integrated documentation photoreceptors. J. Neurosci. 19: 8799–8807.resource for protein families, domains and functional sites. Nu- Cimbora, D. M., and S. Sakonju, 1995 Drosophila midgut morpho-cleic Acids Res. 29: 37–40. genesis requires the function of the segmentation gene odd-paired.

Armstrong, D. D., 2001 Rett syndrome neuropathology review Dev. Biol. 169: 580–595.2000. Brain Dev. 23 (Suppl. 1): S72–S76. Clayton-Smith, J., and L. Laan, 2003 Angelman syndrome: a re-

Bat-haee, M. A., 2001 A longitudinal study of active treatment of view of the clinical and genetic aspects. J. Med. Genet. 40: 87–95.adaptive skills of individuals with profound mental retardation. Cohen-Cory, S., 2002 The developing synapse: construction andPsychol. Rep. 89: 345–354. modulation of synaptic structures and circuits. Science 298: 770–

Bauman, M. L., and T. L. Kemper, 1982 Morphologic and histoana- 776.tomic observations of the brain in untreated human phenylketo- Connolly, J. B., I. J. Roberts, J. D. Armstrong, K. Kaiser, M.nuria. Acta Neuropathol. 58: 55–63. Forte et al., 1996 Associative learning disrupted by impaired

Bienvenu, T., V. des Portes, A. Saint Martin, N. McDonell, P. Gs signaling in Drosophila mushroom bodies. Science 274: 2104–Billuart et al. 1998 Non-specific X-linked semidominant men- 2107.tal retardation by mutations in a Rab GDP-dissociation inhibitor. Couvert, P., T. Bienvenu, C. Aquaviva, K. Poirier, C. Moraine et al.,Hum. Mol. Genet. 7: 1311–1315. 2001 MECP2 is highly mutated in X-linked mental retardation.

Bienvenu, T., V. des Portes, N. McDonell, A. Carrie, R. Zemni, Hum. Mol. Genet. 10: 941–946.et al. 2000 Missense mutation in PAK3, R67C, causes X-linked Cox, T. C., L. R. Allen, L. L. Cox, B. Hopwood, B. Goodwin etnonspecific mental retardation. Am. J. Med. Genet. 93: 294–298. al., 2000 New mutations in MID1 provide support for loss of

Billuart, P., T. Bienvenu, N. Ronce, V. des Portes, M. C. Vinet, function as the cause of X-linked Opitz syndrome. Hum. Mol.et al. 1998 Oligophrenin-1 encodes a rhoGAP protein involved Genet. 9: 2553–2562.in X-linked mental retardation. Nature 392: 923–926. Daily, D. K., H. H. Ardinger and G. E. Holmes, 2000 Identification

Billuart, P., C. G. Winter, A. Maresh, X. Zhao and L. Luo, 2001 and evaluation of mental retardation. Am. Fam. Physician 61:Regulating axon branch stability: the role of p190 RhoGAP in 1059–1067.repressing a retraction signaling pathway. Cell 107: 195–207. Dashman, T., and C. Sansaricq, 1993 Nutrition in the management

Boda, B., C. Mas and D. Muller, 2002 Activity-dependent regula- of inborn errors of metabolism. Clin. Lab. Med. 13: 407–432.tion of genes implicated in X-linked non-specific mental retarda- Davila-Gutierrez, G., 2002 Agenesis and dysgenesis of the corpustion. Neuroscience 114: 13–17. callosum. Semin. Pediatr. Neurol. 9: 292–301.

Bokel, C., and N. H. Brown, 2002 Integrins in development: mov- Dearborn, R., Q. He, S. Kunes and Y. Dai, 2002 Eph receptoring on, responding to, and sticking to the extracellular matrix. tyrosine kinase-mediated formation of a topographic map in theDev. Cell 3: 311–321. Drosophila visual system. J. Neurosci. 22: 1338–1349.

Bond, J., E. Roberts, G. H. Mochida, D. J. Hampshire, S. Scott et Dockendorff, T. C., H. S. Su, S. M. McBride, Z. Yang, C. H. Choial., 2002 ASPM is a major determinant of cerebral cortical size. et al., 2002 Drosophila lacking dfmr1 activity show defects inNat. Genet. 32: 316–320. circadian output and fail to maintain courtship interest. Neuron

Bonini, N. M., Q. T. Bui, G. L. Gray-Board and J. M. Warrick, 1997 34: 973–984.The Drosophila eyes absent gene directs ectopic eye formation in Dosen, A., and K. Day (Editors), 2001 Treating Mental Illness anda pathway conserved between flies and vertebrates. Development Behavior Disorders in Children and Adults with Mental Retardation.124: 4819–4826. American Psychiatric Press, Washington, DC.

Boyadjiev, S. A., and E. W. Jabs, 2000 Online Mendelian Inheri- Douglas, J., S. Hanks, I. K. Temple, S. Davies, A. Murray et al.,tance in Man (OMIM) as a knowledge base for human develop- 2003 NSD1 mutations are the major cause of Sotos syndromemental disorders. Clin. Genet. 57: 253–266. and occur in some cases of Weaver syndrome but are rare in

Brody, T., C. Stivers, J. Nagle and W. F. Odenwald, 2002 Identi- other overgrowth phenotypes. Am. J. Hum. Genet. 72: 132–143.fication of novel Drosophila neural precursor genes using a differ- Dubnau, J., and T. Tully, 1998 Gene discovery in Drosophila: newential embryonic head cDNA screen. Mech. Dev. 113: 41–59. insights for learning and memory. Annu. Rev. Neurosci. 21: 407–

Brown, L. Y., S. Odent, V. David, M. Blayau, C. Dubourg et al., 444.2001 Holoprosencephaly due to mutations in ZIC2: alanine Dubnau, J., A. S. Chiang, L. Grady, H. Barditch, S. Gossweiler ettract expansion mutations may be caused by parental somatic al., 2003 The staufen/pumilio pathway is involved in Drosophilarecombination. Hum. Mol. Genet. 10: 791–796. long-term memory. Curr. Biol. 13: 286–296.Buescher, M., F. S. Hing and W. Chia, 2002 Formation of neuro-Durand, D., 2003 Vertebrate evolution: doubling and shuffling withblasts in the embryonic central nervous system of Drosophila mela-

a full deck. Trends Genet. 19: 2–5.nogaster is controlled by SoxNeuro. Development 129: 4193–4203.Elson, E., R. Perveen, D. Donnai, S. Wall and G. C. M. Black, 2002Butler, F. M., S. P. Miller, K. H. Lee and T. Pierce, 2001 Teaching

De novo GLI3 mutation in acrocallosal syndrome: broadening themathematics to students with mild-to-moderate mental retarda-phenotypic spectrum of GLI3 defects and overlap with murinetion: a review of the literature. Ment. Retard. 39: 20–31.models. J. Med. Genet. 39: 804–806.Canal, I., A. Acebes and A. Ferrus, 1998 Single neuron mosaics

Eng, L. F., R. S. Ghirnikar and Y. L. Lee, 2000 Glial fibrillary acidicof the Drosophila gigas mutant project beyond normal targetsprotein: GFAP-thirty-one years (1969–2000). Neurochem. Res.and modify behavior. J. Neurosci. 18: 999–1008.25: 1439–1451.Cantani, A., and D. Gagliesi, 1998 Rubinstein-Taybi syndrome.

Faiella, A., S. Brunelli, T. Granata, L. D’Incerti, R. Cardini etReview of 732 cases and analysis of the typical traits. Eur. Rev.al., 1997 A number of schizencephaly patients including twoMed. Pharmacol. Sci. 2: 81–87.brothers are heterozygous for germline mutations in the homeo-Cardoso, C., R. J. Leventer, J. J. Dowling, H. L. Ward, J. Chung etbox gene EMX2. Eur. J. Hum. Genet. 5: 186–190.al., 2002 Clinical and molecular basis of classical lissencephaly:

Feany, M. B., and W. W. Bender, 2000 A Drosophila model ofmutations in the LIS1 gene (PAFAH1B1). Hum. Mutat. 19: 4–15.Parkinson’s disease. Nature 404: 394–398.Cheadle, J. P., H. Gill, N. Fleming, J. Maynard, A. Kerr et al., 2000

Feinstein, A., J. Friedman and M. Schewach-Millet, 1988 Pachy-Long-read sequence analysis of the MECP2 gene in Rett syndromeonychia congenita. J. Am. Acad. Dermatol. 19: 705–711.patients: correlation of disease severity with mutation type and

Felipo, V., and R. F. Butterworth, 2002 Neurobiology of ammo-location. Hum. Mol. Genet. 9: 1119–1129.nia. Prog. Neurobiol. 67: 259–279.Chelly, J., 1999 Breakthroughs in molecular and cellular mecha-

Fleming, R. J., T. N. Scottgale, R. J. Diederich and S. Artavanis-nisms underlying X-linked mental retardation. Hum. Mol. Genet.Tsakonas, 1990 The gene Serrate encodes a putative EGF-like8: 1833–1838.transmembrane protein essential for proper ectodermal develop-Chiurazzi, P., B. C. Hamel and G. Neri, 2001 XLMR genes: updatement in Drosophila melanogaster. Genes Dev. 4: 2188–2201.2000. Eur. J. Hum. Genet. 9: 71–81.

FlyBase Consortium, 2002 The FlyBase database of the DrosophilaChow, C. W., and D. R. Thorburn, 2000 Morphological correlatesgenome projects and community literature. Nucleic Acids Res.of mitochondrial dysfunction in children. Hum. Reprod. 1530: 106–108.(Suppl. 2): 68–78.

Chyb, S., W. Hevers, M. Forte, W. J. Wolfgang, Z. Selinger et al., Fortini, M. E., M. P. Skupski, M. S. Boguski and I. K. Hariharan,


2000 A survey of human disease gene counterparts in the Dro- Huttenlocher, P. R., 2000 The neuropathology of phenylketonu-ria: human and animal studies. Eur. J. Pediatr. 159 (Suppl. 2):sophila genome. J. Cell Biol. 150: F23–F30.

Fox, J. W., E. D. Lamperti, Y. Z. Eksioglu, S. E. Hong, Y. Feng et S102–S106.Ingham, P. W., and A. P. McMahon, 2001 Hedgehog signaling inal., 1998 Mutations in filamin 1 prevent migration of cerebral

cortical neurons in human periventricular heterotopia. Neuron animal development: paradigms and principles. Genes Dev. 15:3059–3087.21: 1315–1325.

Frints, S., G. Froyen, P. Marynen and J. P. Fryns, 2002 X-linked Inoue, S. B., M. Shimoda, I. Nishinokubi, M. C. Siomi, M. Okamuraet al., 2002 A role for the Drosophila fragile X-related gene inmental retardation: vanishing boundaries between non-specific

(MRX) and syndromic (MRXS) forms. Clin. Genet. 62: 423–432. circadian output. Curr. Biol. 12: 1331–1335.Irwin, S. A., R. Galvez and W. T. Greenough, 2000 Dendritic spineFriocourt, G., A. Koulakoff, P. Chafey, D. Boucher, F. Faucher-

eau et al., 2003 Doublecortin functions at the extremities of structural anomalies in fragile-X mental retardation syndrome.Cereb. Cortex 10: 1038–1044.growing neuronal processes. Cereb. Cortex 13: 620–626.

Garcia-Alonso, L., S. Romani and F. Jimenez, 2000 The EGF and Ishizuka, A., M. C. Siomi and H. Siomi, 2002 A Drosophila fragileX protein interacts with components of RNAi and ribosomalFGF receptors mediate neuroglian function to control growth

cone decisions during sensory axon guidance in Drosophila. Neu- proteins. Genes Dev. 16: 2497–2508.Jackson, G. R., I. Salecker, X. Dong, X. Yao, N. Arnheim et al.,ron 28: 741–752.

Gene Ontology Consortium, 2001 Creating the gene ontology 1998 Polyglutamine-expanded human huntingtin transgenes in-duce degeneration of Drosophila photoreceptor neurons. Neu-resource: design and implementation. Genome Res. 11: 1425–

1433. ron 21: 633–642.Jacobsen, N. J. O., I. Lyons, B. Hoogendoorn, S. Burge, P.-Y. KwokGibbons, R. J., and D. R. Higgs, 2000 Molecular-clinical spectrum

of the ATR-X syndrome. Am. J. Med. Genet. 97: 204–212. et al., 1999 ATP2A2 mutations in Darier’s disease and theirrelationship to neuropsychiatric phenotypes. Hum. Mol. Genet.Gibbons, R. J., D. J. Picketts, L. Villard and D. R. Higgs, 1995

Mutations in a putative global transcriptional regulator cause 8: 1631–1636.Jacquot, S., M. Zeniou, R. Touraine and A. Hanauer, 2002X-linked mental retardation with alpha-thalassemia (ATR-X syn-

drome). Cell 80: 837–845. X-linked Coffin-Lowry syndrome (CLS, MIM 303600, RPS6KA3gene, protein product known under various names: pp90rsk2,Gilmore, E. C., R. S. Nowakowski, V. S. Caviness and K. Herrup,

2000 Cell birth, cell death, cell diversity and DNA breaks: How RSK2, ISPK, MAPKAP1). Eur. J. Hum. Genet. 10: 2–5.Jin, P., and S. T. Warren, 2003 New insights into fragile X syndrome:do they all fit together? Trends Neurosci. 23: 100–105.

Giordano, E., I. Peluso, S. Senger and M. Furia, 1999 minifly, a from molecules to neurobehaviors. Trends Biochem. Sci. 28:152–158.Drosophila gene required for ribosome biogenesis. J. Cell Biol.

144: 1123–1133. Johnson, A., 2002 Alexander disease: a review and the gene. Int. J.Dev. Neurosci. 20: 391–394.Goldman, R. D., Y. Gruenbaum, R. D. Moir, D. K. Shumaker and

T. P. Spann, 2002 Nuclear lamins: building blocks of nuclear Johnston, S. H., C. Rauskolb, R. Wilson, B. Prabhakaran, K. D.Irvine et al., 1997 A family of mammalian Fringe genes impli-architecture. Genes Dev. 16: 533–547.

Greener, M. J., and R. G. Roberts, 2000 Conservation of compo- cated in boundary determination and the Notch pathway. Devel-opment 124: 2245–2254.nents of the dystrophin complex in Drosophila. FEBS Lett. 482:

13–18. Jones, K. J., G. Morgan, H. Johnston, V. Tobias, R. A. Ouvrier et al.,2001 The expanding phenotype of laminin �2 chain (merosin)Gruters, A., A. Jenner and H. Krude, 2002 Long-term conse-

quences of congenital hypothyroidism in the era of screening abnormalities: case series and review. J. Med. Genet. 38: 649–657.Kabra, M., and S. Gulati, 2003 Mental retardation. Indian J. Pedi-programmes. Best Pract. Res. Clin. Endocrinol. Metab. 16: 369–

382. atr. 70: 153–158.Kahler, S. G., and M. C. Fahey, 2003 Metabolic disorders andGu, Y., N. A. Hukriede and R. J. Fleming, 1995 Serrate expression

can functionally replace Delta activity during neuroblast segrega- mental retardation. Am. J. Med. Genet. 117C: 31–41.Katsanis, N., S. J. Ansley, J. L. Badano, E. R. Eichers, R. A. Lewistion in the Drosophila embryo. Development 121: 855–865.

Guo, H. F., J. Tong, F. Hannan, L. Luo and Y. Zhong, 2000 A et al., 2001 Triallelic inheritance in Bardet-Biedl syndrome, aMendelian recessive disorder. Science 293: 2256–2259.neurofibromatosis-1-regulated pathway is required for learning

in Drosophila. Nature 403: 895–898. Kaufmann, W. E., and H. W. Moser, 2000 Dendritic anomalies indisorders associated with mental retardation. Cereb. Cortex 10:Hall, S. G., and A. J. Bieber, 1997 Mutations in the Drosophila

neuroglian cell adhesion molecule affect motor neuron pathfind- 981–991.Kaytor, M. D., and H. T. Orr, 2001 RNA targets of the fragile Xing and peripheral nervous system patterning. J. Neurobiol. 32:

325–340. protein. Cell 107: 555–557.Kazantsev, A., H. A. Walker, N. Slepko, J. E. Bear, E. PreisingerHammer, S., N. Dorrani, J. Dragich, S. Kudo and C. Schanen,

2002 The phenotypic consequences of MECP2 mutations ex- et al., 2002 A bivalent Huntingtin binding peptide suppressespolyglutamine aggregation and pathogenesis in Drosophila. Nat.tend beyond Rett syndrome. Ment. Retard. Dev. Disabil. Res. Rev.

8: 94–98. Genet. 30: 367–376.Kinsbourne, M., and W. D. Graf, 2000 Disorders of mental develop-Hamosh, A., A. F. Scott, J. Amberger, C. Bocchini, D. Valle et

al., 2002 Online Mendelian Inheritance in Man (OMIM), a ment, pp. 1155–1211 in Child Neurology, edited by J. H. Menkesand H. B. Sarnat. Lippincott Williams & Wilkins, Philadelphia.knowledge base of human genes and genetic disorders. Nucleic

Acids Res. 30: 52–55. Kitamura, K., M. Yanazawa, N. Sugiyama, H. Miura, A. Iizuka-Kogo et al., 2002 Mutation of ARX causes abnormal develop-Hanauer, A., and I. D. Young, 2002 Coffin-Lowry syndrome: clinical

and molecular features. J. Med. Genet. 39: 705–713. ment of forebrain and testes in mice and X-linked lissencephalywith abnormal genitalia in humans. Nat. Genet. 32: 359–369.Hing, H., J. Xiao, N. Harden, L. Lim and S. L. Zipursky, 1999 Pak

functions downstream of Dock to regulate photoreceptor axon Klambt, C., L. Glazer and B. Z. Shilo, 1992 breathless, a Drosoph-ila FGF receptor homolog, is essential for migration of trachealguidance in Drosophila. Cell 97: 853–863.

Hoang, B., and A. Chiba, 1998 Genetic analysis on the role of and specific midline glial cells. Genes Dev. 6: 1668–1678.Koeppen, A. H., and Y. Robitaille, 2002 Pelizaeus-Merzbacher dis-integrin during axon guidance in Drosophila. J. Neurosci. 18:

7847–7855. ease. J. Neuropathol. Exp. Neurol. 61: 747–759.Kopp, P., 2002 Perspective: genetic defects in the etiology of congeni-Huang, X., and W. Miller, 1991 A time-efficient, linear-space local

similarity algorithm. Adv. Appl. Math. 12: 337–357. tal hypothyroidism. Endocrinology 143: 2019–2024.Koyabu, Y., K. Nakata, K. Mizugishi, J. Aruga and K. Mikoshiba,Huang, Z., and S. Kunes, 1998 Signals transmitted along retinal

axons in Drosophila: hedgehog signal reception and the cell 2001 Physical and functional interaction between Zic and Gliproteins. J. Biol. Chem. 276: 6889–6892.circuitry of lamina cartridge assembly. Development 125: 3753–

3764. Kraft, R., R. B. Levine and L. L. Restifo, 1998 The steroid hor-mone 20-hydroxyecdysone enhances neurite growth of Drosoph-Huopio, H., S.-L. Shyng, T. Otonkoski and C. G. Nichols, 2002

KATP channels and insulin secretion disorders. Am. J. Physiol. ila mushroom body neurons isolated during metamorphosis. J.Neurosci. 18: 8886–8899.Endocrinol. Metab. 283: E207–E216.


Krantz, I. D., R. P. Colliton, A. Genin, E. B. Rand, L. Li et al., Lynch, T. M., and D. H. Gutmann, 2002 Neurofibromatosis 1.Neurol. Clin. 20: 841–865.1998 Spectrum and frequency of jagged1 (JAG1) mutations in

Alagille syndrome patients and their families. Am. J. Hum. Genet. Ma, K., K. M. Vattem and R. C. Wek, 2002 Dimerization and releaseof molecular chaperone inhibition facilitate activation of eukaryo-62: 1361–1369.

Kugler, W., and M. Lakomek, 2000 Glucose-6-phosphate isomerase tic initiation factor-2 kinase in response to endoplasmic reticulumstress. J. Biol. Chem. 277: 18728–18735.deficiency. Bailliere’s Best Pract. Res. Clin. Haematol. 13: 89–101.

Kutsche, K., H. Yntema, A. Brandt, I. Jantke, H. G. Nothwang et MacIver, B., A. McCormack, R. Slee and M. Bownes, 1998 Identi-fication of an essential gene encoding a class-V unconventionalal., 2000 Mutations in ARHGEF6, encoding a guanine nucleo-

tide exchange factor for Rho GTPases, in patients with X-linked myosin in Drosophila melanogaster. Eur. J. Biochem. 257: 529–537.Maizel, J. V., Jr., and R. P. Lenk, 1981 Enhanced graphic matrixmental retardation. Nat. Genet. 26: 247–250.

Laggerbauer, B., D. Ostareck, E.-M. Keidel, A. Ostareck-Lederer analysis of nucleic acid and protein sequences. Proc. Natl. Acad.Sci. USA 78: 7665–7669.and U. Fischer, 2001 Evidence that fragile X mental retarda-

tion protein is a negative regulator of translation. Hum. Mol. Marek, K. W., N. Ng, R. Fetter, S. Smolik, C. S. Goodman et al.,2000 A genetic analysis of synaptic development: pre- and post-Genet. 10: 329–338.

Laumonnier, F., N. Ronce, B. C. Hamel, P. D. Thomas, J. Lespinasse synaptic dCBP control transmitter release at the Drosophila NMJ.Neuron 25: 537–547.et al., 2002 Transcription factor SOX3 is involved in X-linked

mental retardation with growth hormone deficiency. Am. J. Hum. Marsh, D. J., V. Coulon, K. L. Lunetta, P. Rocca-Serra, P. L.Dahia et al., 1998 Mutation spectrum and genotype-phenotypeGenet. 71: 1450–1455.

Lebel, R. R., M. May, S. Pouls, H. A. Lubs, R. E. Stevenson et analyses in Cowden disease and Bannayan-Zonana syndrome, twohamartoma syndromes with germline PTEN mutation. Hum. Mol.al., 2002 Non-syndromic X-linked mental retardation associated

with a missense mutation (P312L) in the FGD1 gene. Clin. Genet. Genet. 7: 507–515.Martin, D., S. Zusman, X. Li, E. L. Williams, N. Khare et al., 199961: 139–145.

Lee, A., L. Wenjun, K. Xu, B. A. Bogert, K. Su et al., 2003 Control wing blister, a new Drosophila laminin alpha chain requiredfor cell adhesion and migration during embryonic and imaginalof dendritic development by the Drosophila fragile X-related gene

involves the small GTPase Rac1. Development 130: 5543–5552. development. J. Cell Biol. 145: 191–201.Martin, N., J. Jaubert, P. Gounon, E. Salido, G. Haase et al., 2002Leenders, A. G., F. H. Lopes da Silva, W. E. Ghijsen and M. Ver-

hage, 2001 Rab3a is involved in transport of synaptic vesicles A missense mutation in Tbce causes progressive motor neuropathyin mice. Nat. Genet. 32: 443–447.to the active zone in mouse brain nerve terminals. Mol. Biol. Cell

12: 3095–3102. Mattson, M. P., and T. B. Shea, 2003 Folate and homocysteinemetabolism in neural plasticity and neurodegenerative disorders.Lehrke, R., 1972 Theory of X-linkage of major intellectual traits.

Am. J. Ment. Defic. 76: 611–619. Trends Neurosci. 26: 137–146.Mazroui, R., M. E. Huot, S. Tremblay, C. Filion, Y. Labelle et al.,Leonard, H., and X. Wen, 2002 The epidemiology of mental retar-

dation: challenges and opportunities in the new millennium. 2002 Trapping of messenger RNA by fragile X mental retarda-tion protein into cytoplasmic granules induces translational re-Ment. Retard. Dev. Disabil. Res. Rev. 8: 117–134.

Leuzinger, S., F. Hirth, D. Gerlich, D. Acampora, A. Simeone et pression. Hum. Mol. Genet. 11: 3007–3017.McLaren, J., and S. E. Bryson, 1987 Review of recent epidemiologi-al., 1998 Equivalence of the fly orthodenticle gene and the human

OTX genes in embryonic brain development of Drosophila. Devel- cal studies of mental retardation: prevalence, associated disordersand etiology. Am. J. Ment. Retard. 92: 243–254.opment 125: 1703–1710.

Levy, H. L., 1999 Phenylketonuria: old disease, new approach to Merienne, K., S. Jacquot, S. Pannetier, M. Zeniou, A. Bankier etal., 1999 A missense mutation in RPS6KA3 (RSK2) responsibletreatment. Proc. Natl. Acad. Sci. USA 96: 1811–1813.

Li, L., F. Liu and A. H. Ross, 2003 PTEN regulation of neural for non-specific mental retardation. Nat. Genet. 22: 13–14.Ming, J. E., E. Roessler and M. Muenke, 1998 Human develop-development and CNS stem cells. J. Cell. Biochem. 88: 24–28.

Li, M., M. Serr, K. Edwards, S. Ludmann, D. Yamamoto et al., 1999 mental disorders and the Sonic hedgehog pathway. Mol. Med.Today 4: 343–349.Filamin is required for ring canal assembly and actin organization

during Drosophila oogenesis. J. Cell Biol. 146: 1061–1073. Mizuguchi, M., and S. Takashima, 2001 Neuropathology of tuber-ous sclerosis. Brain Dev. 23: 508–515.Li, M., C. Shuman, Y. L. Fei, E. Cutiongco, H. A. Bender et al., 2001

GPC3 mutation analysis in a spectrum of patients with overgrowth Molinari, F., M. Rio, V. Meskenaite, F. Encha-Razavi, J. Auge et al.,2002 Truncating neurotrypsin mutation in autosomal recessiveexpands the phenotype of Simpson-Golabi-Behmel syndrome.

Am. J. Med. Genet. 102: 161–168. nonsyndromic mental retardation. Science 298: 1779–1781.Morales, J., P. R. Hiesinger, A. J. Schroeder, K. Kume, P. Ver-Lichter-Konecki, U., C. M. Hipke and D. S. Konecki, 1999 Human

phenylalanine hydroxylase gene expression in kidney and other streken et al., 2002 Drosophila fragile X protein, DFXR, regu-lates neuronal morphology and function in the brain. Neuronnonhepatic tissues. Mol. Genet. Metab. 67: 308–316.

Lin, T., B. M. Orrison, S. F. Suchy, R. A. Lewis and R. L. Nussbaum, 34: 961–972.Morley, K. I., and G. W. Montgomery, 2001 The genetics of cogni-1998 Mutations are not uniformly distributed throughout the

OCRL1 gene in Lowe syndrome patients. Mol. Genet. Metab. 64: tive processes: candidate genes in humans and animals. Behav.Genet. 31: 511–531.58–61.

Liu, Z., R. Steward and L. Luo, 2000 Drosophila Lis1 is required Morton, N. E., 1992 Genes for intelligence on the X chromosome.J. Med. Genet. 29: 71.for neuroblast proliferation, dendritic elaboration and axonal

transport. Nat.. Cell Biol. 2: 776–783. Musante, L., H. G. Kehl, F. Majewski, P. Meinecke, S. Schweigeret al., 2003 Spectrum of mutations in PTPN11 and genotype-Lloyd, T. E., P. Verstreken, E. J. Ostrin, A. Phillippi, O. Lich-

targe et al., 2000 A genome-wide search for synaptic vesicle phenotype correlation in 96 patients with Noonan syndrome andfive patients with cardio-facio-cutaneous syndrome. Eur. J. Hum.cycle proteins in Drosophila. Neuron 26: 45–50.

Long, E. S., and R. G. Miltenberger, 1998 A review of behavioral Genet. 11: 201–206.Nagai, T., J. Aruga, O. Minowa, T. Sugimoto, Y. Ohno et al., 2000and pharmacological treatments for habit disorders in individuals

with mental retardation. J. Behav. Ther. Exp. Psychiatry 29: 143– Zic2 regulates the kinetics of neurulation. Proc. Natl. Acad. Sci.USA 97: 1618–1623.156.

Lubs, H. A., 1999 The other side of the coin: a hypothesis concerning Nagao, T., S. Leuzinger, D. Acampora, A. Simeone, R. Finkelsteinet al., 1998 Developmental rescue of Drosophila cephalic defectsthe importance of genes for high intelligence and evolution on

the X chromosome. Am. J. Med. Genet. 85: 206–208. by the human Otx genes. Proc. Natl. Acad. Sci. USA 95: 3737–3742.Nakato, H., T. A. Futch and S. B. Selleck, 1995 The divisionLuckasson, R., D. L. Coulter, E. A. Polloway, S. Reiss, R. L.

Schalock et al., 1992 Mental Retardation: Definition, Classification, abnormally delayed (dally) gene: a putative integral membrane pro-teoglycan required for cell division patterning during postembry-and Systems of Support. American Association on Mental Retarda-

tion, Washington, DC. onic development of the nervous system in Drosophila. Develop-ment 121: 3687–3702.Luo, Y., J. M. Long, C. Lu, S. L. Chan, E. L. Spangler et al., 2002

A link between maze learning and hippocampal expression of Newfeld, S. J., and N. T. Takaesu, 2002 An analysis using the hobogenetic system reveals that combinatorial signaling by the Dppneuroleukin and its receptor gp78. J. Neurochem. 80: 354–361.


and Wg pathways regulates dpp expression in leading edge cells producing neurons in flies: growth and diabetic phenotypes.Science 296: 1118–1120.of the dorsal ectoderm in Drosophila melanogaster. Genetics 161:

685–692. Sacksteder, K. A., B. J. Biery, J. C. Morrell, B. K. Goodman, B. V.Geisbrecht et al., 2000 Identification of the alpha-aminoadipicOdent, S., T. Attie-Bitach, M. Blayau, M. Mathieu, J. Auge et al.,

1999 Expression of the Sonic hedgehog (SHH) gene during early semialdehyde synthase gene, which is defective in familial hyper-lysinemia. Am. J. Hum. Genet. 66: 1736–1743.human development and phenotypic expression of new muta-

tions causing holoprosencephaly. Hum. Mol. Genet. 8: 1683– Sanal, O., L. Yel, T. Kucukali, E. Gilbert-Barnes, M. Tardieu etal., 2000 An allelic variant of Griscelli disease: presentation with1689.

Oldham, S., H. Stocker, M. Laffargue, F. Wittwer, M. Wymann et severe hypotonia, mental-motor retardation, and hypopigmenta-tion consistent with Elejalde syndrome (neuroectodermal mela-al., 2002 The Drosophila insulin/IGF receptor controls growth

and size by modulating PtdInsP(3) levels. Development 129: nolysosomal disorder). J. Neurol. 247: 570–572.Seimiya, M., and W. J. Gehring, 2000 The Drosophila homeobox4103–4109.

Olson, E. C., and C. A. Walsh, 2002 Smooth, rough and upside- gene optix is capable of inducing ectopic eyes by an eyeless-indepen-dent mechanism. Development 127: 1879–1886.down neocortical development. Curr. Opin. Genet. Dev. 12: 320–

327. Servidei, S., 2001 Mitochondrial encephalomyopathies: gene muta-tion. Neuromuscul. Disord. 11: 332–337.Orrico, A., C. Lam, L. Galli, M. T. Dotti, G. Hayek et al., 2000

MECP2 mutation in male patients with non-specific X-linked men- Shapiro, B. L., 1999 The Down syndrome critical region. J. Neural.Transm. 57 (Suppl.): 41–60.tal retardation. FEBS Lett. 481: 285–288.

Overton, P. M., L. A. Meadows, J. Urban and S. Russell, 2002 Shishido, E., N. Ono, T. Kojima and K. Saigo, 1997 Requirementsof DFR1/Heartless, a mesoderm-specific Drosophila FGF-recep-Evidence for differential and redundant function of the Sox

genes Dichaete and SoxN during CNS development in Drosophila. tor, for the formation of heart, visceral and somatic muscles, andensheathing of longitudinal axon tracts in CNS. DevelopmentDevelopment 129: 4219–4228.

Padgett, R. W., J. M. Wozney and W. M. Gelbart, 1993 Human 124: 2119–2128.Stevenson, R. E., C. E. Schwartz and R. J. Schroer, 2000 X-LinkedBMP sequences can confer normal dorsal-ventral patterning in

the Drosophila embryo. Proc. Natl. Acad. Sci. USA 90: 2905–2909. Mental Retardation. Oxford University Press, New York.Stromme, P., M. E. Mangelsdorf, M. A. Shaw, K. M. Lower, S. M.Parvari, R., E. Hershkovitz, N. Grossman, R. Gorodischer, B.

Loeys et al., 2002 Mutation of TBCE causes hypoparathyroidism- Lewis et al., 2002 Mutations in the human ortholog of Aristalesscause X-linked mental retardation and epilepsy. Nat. Genet. 30:retardation-dysmorphism and autosomal recessive Kenny-Caffey

syndrome. Nat. Genet. 32: 448–452. 441–445.Surtees, R., and N. Blau, 2000 The neurochemistry of phenylketo-Pasquier, L., C. Dubourg, M. Blayau, L. Lazaro, B. Le Marec et

al., 2000 A new mutation in the six-domain of SIX3 gene causes nuria. Eur. J. Pediatr. 159 (Suppl. 2): S109–S113.Takagishi, Y., S. Oda, S. Hayasaka, K. Dekker-Ohno, T. Shikataholoprosencephaly. Eur. J. Hum. Genet. 8: 797–800.

Passos-Bueno, M. R., W. R. Wilcox, E. W. Jabs, A. L. Sertie, L. G. et al., 1996 The dilute-lethal (dl) gene attacks a Ca2 store inthe dendritic spine of Purkinje cells in mice. Neurosci. Lett. 215:Alonso et al., 1999 Clinical spectrum of fibroblast growth factor

receptor mutations. Hum. Mutat. 14: 115–125. 169–172.Tapon, N., N. Ito, B. J. Dickson, J. E. Treisman and I. K. Hariharan,Payne, J. A., C. Rivera, J. Voipio and K. Kaila, 2003 Cation-chloride

co-transporters in neuronal communication, development and 2001 The Drosophila tuberous sclerosis complex gene homo-logs restrict cell growth and cell proliferation. Cell 105: 345–355.trauma. Trends Neurosci. 26: 199–206.

Pegoraro, E., F. Cepollaro, P. Prandini, A. Marin, M. Fanin et al., Thompson, C. C., and G. B. Potter, 2000 Thyroid hormone actionin neural development. Cereb. Cortex 10: 939–945.2002 Integrin alpha 7 beta 1 in muscular dystrophy/myopathy

of unknown etiology. Am. J. Pathol. 160: 2135–2143. Toniolo, D., 2000 In search of the MRX genes. Am. J. Med. Genet.97: 221–227.Periz, G., and M. E. Fortini, 1999 Ca2-ATPase function is required

for intracellular trafficking of the Notch receptor in Drosophila. Tsai, H., R. E. Hardisty, C. Rhodes, A. E. Kiernan, P. Roby et al.,2001 The mouse slalom mutant demonstrates a role for Jagged1EMBO J. 18: 5983–5993.

Perkins, L. A., M. R. Johnson, M. B. Melnick and N. Perrimon, in neuroepithelial patterning in the organ of Corti. Hum. Mol.Genet. 10: 507–512.1996 The nonreceptor protein tyrosine phosphatase corkscrew

functions in multiple receptor tyrosine kinase pathways in Dro- Tsuda, M., K. Kamimura, H. Nakato, M. Archer, W. Staatz etal., 1999 The cell-surface proteoglycan Dally regulates Winglesssophila. Dev. Biol. 180: 63–81.

Pinto, S., D. G. Quintana, P. Smith, R. M. Mihalek, Z. H. Hou et signaling in Drosophila. Nature 400: 213–215.Turner, G., 1996 Intelligence and the X chromosome. Lancet 347:al., 1999 latheo encodes a subunit of the origin recognition

complex and disrupts neuronal proliferation and adult olfactory 1814–1815.Turner, G., and M. W. Partington, 1991 Genes for intelligencememory when mutant. Neuron 23: 45–54.

Pomeroy, S. L., and J. Y. H. Kim, 2000 Biology and pathobiology on the X chromosome. J. Med. Genet. 28: 429.Vannucci, R. C., and S. J. Vannucci, 2001 Hypoglycemic brainof neuronal development. Ment. Retard. Dev. Disabil. Res. Rev.

6: 41–46. injury. Semin. Neonatol. 6: 147–155.Vargha-Khadem, F., K. E. Watkins, C. J. Price, J. Ashburner, K. J.Ramakers, G. J., 2002 Rho proteins, mental retardation and the

cellular basis of cognition. Trends Neurosci. 25: 191–199. Alcock et al., 1998 Neural basis of an inherited speech andlanguage disorder. Proc. Natl. Acad. Sci. USA 95: 12695–12700.Reiss, J., S. Gross-Hardt, E. Christensen, P. Schmidt, R. R. Mendel

et al., 2001 A mutation in the gene for the neurotransmitter Venter, J. C., M. D. Adams, E. W. Myers, P. W. Li, R. J. Mural etal., 2001 The sequence of the human genome. Science 291:receptor-clustering protein gephyrin causes a novel form of mo-

lybdenum cofactor deficiency. Am. J. Hum. Genet. 68: 208–213. 1304–1351.Wakefield, J. G., S. Bonaccorsi and M. Gatti, 2001 The Drosoph-Reiter, L.T ., L. Potocki, S. Chien, M. Gribskov and E. Bier, 2001

A systematic analysis of human disease-associated gene sequences ila protein Asp is involved in microtubule organization duringspindle formation and cytokinesis. J. Cell Biol. 153: 637–647.in Drosophila melanogaster. Genome Res. 11: 1114–1125.

Ricard, C. S., J. M. Jakubowski, J. W. Verbsky, M. A. Barbieri, Walkley, S. U., 1998 Cellular pathology of lysosomal storage disor-ders. Brain Pathol. 8: 175–193.W. M. Lewis et al., 2001 Drosophila rab GDI mutants disrupt

development but have normal rab membrane extraction. Genesis Wallach, D., T. U. Arumugam, M. P. Boldin, G. Cantarella, K. A.Ganesh et al., 2002 How are the regulators regulated? The31: 17–29.

Roeleveld, N., G. A. Zielhuis and F. Gabreels, 1997 The preva- search for mechanisms that impose specificity on induction ofcell death and NF-kappaB activation by members of the TNF/lence of mental retardation: a critical review of recent literature.

Dev. Med. Child Neurol. 39: 125–132. NGF receptor family. Arthritis Res. 4: S189–S196.Wallis, D., and M. Muenke, 2000 Mutations in holoprosencephaly.Ropers, H.-H., M. Hoeltzenbein, V. Kalscheuer, H. Yntema, B.

Hamel et al., 2003 Nonsyndromic X-linked mental retardation: Hum. Mutat. 16: 99–108.Wan, L., T. C. Dockendorff, T. A. Jongens and G. Dreyfuss, 2000Where are the missing mutations? Trends Genet. 19: 316–320.

Rulifson, E. J., S. K. Kim and R. Nusse, 2002 Ablation of insulin- Characterization of dFMR1, a Drosophila melanogaster homolog


of the fragile X mental retardation protein. Mol. Cell. Biol. 20: Yager, J., S. Richards, D. S. Hekmat-Scafe, D. D. Hurd, V. Sundare-san et al., 2001 Control of Drosophila perineurial glial growth by8536–8547.interacting neurotransmitter-mediated signaling pathways. Proc.Warrick, J. M., H. L. Paulson, G. L. Gray-Board, Q. T. Bui, K. H.Natl. Acad. Sci. USA 98: 10445–10450.Fischbeck et al., 1998 Expanded polyglutamine protein forms

Yntema, H. G., F. A. Poppelaars, E. Derksen, A. R. Oudakker,nuclear inclusions and causes neural degeneration in Drosophila.T. Van Roosmalen et al., 2002 Expanding phenotype of XNPCell 93: 939–949.mutations: mild to moderate mental retardation. Am. J. Med.Weller, S., and J. Gartner, 2001 Genetic and clinical aspects ofGenet. 110: 243–247.X-linked hydrocephalus (L1 disease): mutations in the L1CAM

Zalfa, F., M. Giorgi, B. Primerano, A. Moro, A. Di Penta et al.,gene. Hum. Mutat. 18: 1–12.2003 The fragile X syndrome protein FMRP associates with BC1Werner, L. A., and L. J. Manseau, 1997 A Drosophila gene withRNA and regulates translation of specific mRNAs at synapses.predicted rhoGEF, pleckstrin homology and SH3 domains isCell 112: 317–327.highly expressed in morphogenic tissues. Gene 187: 107–114.

Zars, T., 2000 Behavioral functions of the insect mushroom bodies.Wisniewski, K. E., N. Zhong and M. Philippart, 2001 Pheno/Curr. Opin. Neurobiol. 10: 790–795.genotypic correlations of neuronal ceroid lipofuscinoses. Neurol-

Zechner, U., M. Wilda, H. Kehrer-Sawatzki, W. Vogel, R. Fundeleogy 57: 576–581.et al., 2001 A high density of X-linked genes for general cognitiveWittle, A. E., K. P. Kamdar and V. Finnerty, 1999 The Drosophilaability: A run-away process shaping human evolution? Trendscinnamon gene is functionally homologous to Arabidopsis cnx1 Genet. 17: 697–701.and has a similar expression pattern to the mammalian gephyrin Zhang, S., L. Xu, J. Lee and T. Xu, 2002 Drosophila atrophin homo-

gene. Mol. Gen. Genet. 261: 672–680. log functions as a transcriptional corepressor in multiple develop-Wolfgang, W. J., A. Hoskote, I. J. H. Roberts, S. Jackson and mental processes. Cell 108: 45–56.

M. Forte, 2001 Genetic analysis of the Drosophila Gs� Gene. Zhang, Y. Q., A. M. Bailey, H. J. Matthies, R. B. Renden, M. A.Genetics 158: 1189–1201. Smith et al., 2001 Drosophila fragile X-related gene regulates

Woolfenden, A. R., G. W. Albers, G. K. Steinberg, J. S. Hahn, the MAP1B homolog Futsch to control synaptic structure andD. C. C. Johnston et al., 1999 Moyamoya syndrome in children function. Cell 107: 591–603.with Alagille syndrome: additional evidence of a vasculopathy.Pediatrics 103: 505–508. Communicating editor: R. S. Hawley


AP

PE

ND

IX

Hum

anm

enta

lre

tard

atio

nge

nes

and

D.

mel

anog

aste

rho

mol

ogs

Mol

ecul

ar-

Gen

eC

hr.

OM

IMfu

nct

ion

GO

Dro

soph

ilaFl

yBas

eB

LA

STP

sym

bola

Gen

en

ame

arm

bC

linic

aldi

sord

erc

no.

cate

gory

dB

iolo

gica

lfu

nct

ion

(s)e

hom

olog

(s)f

no.

gE

-val

ueh

AA

SS�

-Am

inoa

dipi

c7q

Hyp

erly

sin

emia

6051

13O

xido

redu

ctas

eM

etab

olic

(am

ino

acid

):B

EST

:CK

0231

800

2568

7�

300

sem

iald

ehyd

esy

nth

ase

MR

2sy

stem

icto

xici

tyA

BA

T4-

Am

inob

utyr

ate

16p

Inbo

rner

ror

ofG

AB

A13

7150

Tra

nsf

eras

eC

NS

deve

lopm

ent/

CG

7433

(&)

0036

927

�14

7am

inot

ran

sfer

ase

met

abol

ism

fun

ctio

n:

neu

rotr

ansm

issi

on(G

AB

A)

AB

CC

8A

TP-

bin

din

gca

sset

te,

11p

Hyp

erin

sulin

emic

6005

09R

ecep

tor

En

docr

ine

(pan

crea

s):

[CG

7627

,oth

ers]

0032

026

�15

1(S

UR

1)su

bfam

ilyC

,m

embe

r8

hyp

ogly

cem

iaof

MR

2sy

stem

icfu

elin

fan

cyde

fici

ency

AC

OX

1A

cyl-c

oen

zym

eA

17q

Pseu

don

eon

atal

2644

70O

xido

redu

ctas

eM

etab

olic

(fat

tyac

id):

BcD

NA

:GH

0748

5,00

2757

2�

155

oxid

ase

1ad

ren

oleu

kody

stro

phy

MR

2lo

cal

toxi

city

oth

ers

(glia

:m

yelin

)A

DA

•••

Ade

nos

ine

deam

inas

e20

qA

DA

-sev

ere

com

bin

ed10

2700

Hyd

rola

seM

etab

olic

(pur

ine)

:?M

RA

deno

sine

0037

661

�14

imm

unod

efici

ency

2lo

cal

toxi

city

;de

amin

ase

?neu

rom

odul

atio

nA

DSL

Ade

nyl

osuc

cin

ate

lyas

e22

qSu

ccin

ylpu

rin

emic

1030

50L

yase

Met

abol

ic(p

urin

eC

G35

9000

3846

7�

179

auti

smsy

nth

esis

):?M

R2

syst

emic

toxi

city

AG

AA

spar

tylg

luco

sam

inid

ase

4qA

spar

tylg

luco

sam

inur

ia20

8400

Hyd

rola

seL

ysos

omal

path

way

CG

1827

,00

3343

1�

83(g

lyco

prot

ein

):C

G10

474

MR

2lo

cal

toxi

city

(neu

ron

)A

GT

R2

An

giot

ensi

nII

rece

ptor

Xq

X-li

nke

dM

R30

0034

Rec

epto

rSi

gnal

ing

path

way

[Tak

r99D

,00

0462

2�

18ty

pe2

(GPC

R):

flui

dot

her

s]ba

lan

ce;

CN

Sde

velo

pmen

t/fu

nct

ion

AK

1A

den

ylat

eki

nas

e1

9qH

emol

ytic

anem

iadu

e10

3000

Kin

ase

Met

abol

ic(p

urin

eA

deny

late

0022

709

�45

toA

K1

defi

cien

cyh

omeo

stas

is):

MR

kina

se-1

(&)

caus

eun

know

nA

LD

H3A

2A

ldeh

yde

deh

ydro

gen

ase

17p

Sjog

ren

-Lar

sson

2702

00O

xido

redu

ctas

eM

etab

olic

(fat

tyac

idA

ldh-

III

(&)

0010

548

�10

53A

2sy

ndr

ome

syn

thes

is):

CN

Sde

velo

pmen

t/fu

nct

ion

AL

DH

4A1

Ald

ehyd

ede

hyd

roge

nas

e1p

Hyp

erpr

olin

emia

type

II60

6811

Oxi

dore

duct

ase

Met

abol

ic(a

min

oac

id):

CG

7145

(&)

0037

138

�30

04A

1M

Rca

use

unkn

own

AL

DH

5A1

Ald

ehyd

ede

hyd

roge

nas

e6p

Inbo

rner

ror

ofG

AB

A27

1980

Oxi

dore

duct

ase

Neu

rotr

ansm

issi

onC

G46

85(&

)00

3934

9�

128

5A1

met

abol

ism

(GA

BA

)

(con

tinue

d)


AP

PE

ND

IX

(Con

tinu

ed)

Mol

ecul

ar-

Gen

eC

hr.

OM

IMfu

nct

ion

GO

Dro

soph

ilaFl

yBas

eB

LA

STP

sym

bola

Gen

en

ame

arm

bC

linic

aldi

sord

erc

no.

cate

gory

dB

iolo

gica

lfu

nct

ion

(s)e

hom

olog

(s)f

no.

gE

-val

ueh

AL

DO

AA

ldol

ase

A16

qH

emol

ytic

anem

iadu

eto

1038

50L

yase

Met

abol

ic:

gen

eral

cell

Ald

olas

e,C

G54

3200

0006

4�

131

AL

DO

Ade

fici

ency

inte

grit

yA

LG

2H

omol

ogof

yeas

t9q

Con

gen

ital

diso

rder

of60

7905

Tra

nsf

eras

ePr

otei

nm

odifi

cati

onC

G12

91(&

)00

3540

1�

104

Asp

arag

ineL

inke

dG

ene2

glyc

osyl

atio

nty

peIi

(gly

cosy

lati

on):

CN

Sde

velo

pmen

t/fu

nct

ion

AL

G3

Hom

olog

ofye

ast

3qC

onge

nit

aldi

sord

erof

6011

10T

ran

sfer

ase

Prot

ein

mod

ifica

tion

leth

al(2

)ne

ighb

or00

1129

7�

55(N

OT

65L

)A

spar

agin

eL

inke

dgl

ycos

ylat

ion

type

Id(g

lyco

syla

tion

):C

NS

oftid

Gen

e3

deve

lopm

ent/

fun

ctio

nA

LG

6H

omol

ogof

yeas

t1p

Con

gen

ital

diso

rder

of60

4566

Tra

nsf

eras

ePr

otei

nm

odifi

cati

onC

G50

9100

3223

4�

76A

spar

agin

eL

inke

dgl

ycos

ylat

ion

type

Ic(g

lyco

syla

tion

):C

NS

Gen

e6

deve

lopm

ent/

fun

ctio

nA

LG

12H

omol

ogof

yeas

t22

qC

onge

nit

aldi

sord

erof

6071

44T

ran

sfer

ase

Prot

ein

mod

ifica

tion

CG

8412

0037

743

�98

Asp

arag

ine

Lin

ked

glyc

osyl

atio

nty

peIg

(gly

cosy

lati

on):

CN

SG

ene

12de

velo

pmen

t/fu

nct

ion

AM

TA

min

omet

hyl

tran

sfer

ase

3pG

lyci

ne

ence

phal

opat

hy

2383

10T

ran

sfer

ase

Met

abol

ic(a

min

oac

id):

CG

6415

0032

287

�10

0M

R2

neu

ro/g

lial

toxi

city

(neu

rotr

ansm

issi

on)

AR

G1

Arg

inas

e6q

Arg

inin

emia

2078

00H

ydro

lase

Met

abol

ic(u

rea

cycl

e):

argi

nase

0023

535

�60

MR

2sy

stem

icto

xici

tyA

RH

GEF

6R

ho

guan

ine

nuc

leot

ide

Xq

MR

X46

3002

67R

ecep

tor

Sign

alin

gpa

thw

ayrt

GEF

(&¶

)00

1580

3�

90(P

IXA

)ex

chan

gefa

ctor

6si

gnal

ing

(in

tegr

in):

neu

ron

alpr

otei

nde

velo

pmen

t/pl

asti

city

AR

SAA

ryls

ulfa

tase

A22

qM

etac

hro

mat

ic25

0100

Hyd

rola

seL

ysos

omal

path

way

CG

3219

1,00

5219

1�

23le

ukod

ystr

oph

y(g

lyco

lipid

):M

R2

oth

ers

(*)

loca

lto

xici

ty(g

lia:

mye

lin)

AR

XA

rist

ales

s-re

late

dX

pM

RX

36;W

est

syn

drom

e;30

0382

Tra

nsc

ript

ion

CN

Sde

velo

pmen

t/Pv

uII-P

stI

0023

489

�29

hom

eobo

x,X

-lin

ked

Part

ingt

onsy

ndr

ome;

regu

lato

rfu

nct

ion

:n

euro

nal

hom

olog

y13

,lis

sen

ceph

aly

mig

rati

onot

her

sA

SAH

N-A

cyls

phin

gosi

ne

8pFa

rber

2280

00H

ydro

lase

Lys

osom

alpa

thw

ayN

one

——

amid

ohyd

rola

selip

ogra

nul

omat

osis

(gly

colip

id):

MR

2(c

eram

idas

e)lo

calt

oxic

ity

(neu

ron

)

(con

tinue

d)


AP

PE

ND

IX

(Con

tinu

ed)

Mol

ecul

ar-

Gen

eC

hr.

OM

IMfu

nct

ion

GO

Dro

soph

ilaFl

yBas

eB

LA

STP

sym

bola

Gen

en

ame

arm

bC

linic

aldi

sord

erc

no.

cate

gory

dB

iolo

gica

lfu

nct

ion

(s)e

hom

olog

(s)f

no.

gE

-val

ueh

ASL

Arg

inin

osuc

cin

ate

lyas

e7q

Arg

inin

osuc

cin

i-20

7900

Lya

seM

etab

olic

(ure

acy

cle)

:C

G95

1000

3207

6�

106

caci

duri

aM

R2

syst

emic

toxi

city

ASP

AA

spar

toac

ycla

se17

pC

anav

andi

seas

e27

1900

Hyd

rola

seM

etab

olic

:gl

ial

Non

e—

—de

velo

pmen

t/fu

nct

ion

;M

R2

loca

lto

xici

ty(m

yelin

)A

SPM

Abn

orm

alsp

indl

e-lik

e,1q

Prim

ary

mic

roce

phal

y5

6054

81Pr

otei

nbi

ndi

ng

CN

Sde

velo

pmen

t/ab

norm

al00

0014

0�

54m

icro

ceph

aly-

fun

ctio

n:

spin

dle

(&¶

)as

soci

ated

neu

roge

nes

isA

SSA

rgin

inos

ucci

nat

e9q

Cla

ssic

citr

ullin

emia

6034

70L

igas

eM

etab

olic

(ure

acy

cle)

:B

G:D

S000

04.1

400

2656

5�

121

syn

thet

ase

(typ

eI)

MR

2sy

stem

icto

xici

tyA

TP2

A2

AT

Pase

,C

a(2

) -12

qD

arie

r-W

hit

edi

seas

e10

8740

Tra

nsp

orte

rSi

gnal

ing

path

way

Cal

cium

AT

Pase

at00

0455

1�

300

tran

spor

tin

g,(c

alci

um):

cell

60A

(&¶

)sl

ow-tw

itch

adh

esio

n(s

kin

);M

Rca

use

unkn

own

AT

P7A

Cu2

-tran

spor

tin

gX

qM

enke

ssy

ndr

ome;

3000

11T

ran

spor

ter

Met

abol

ic:

CN

SC

G18

86(&

)00

3034

3�

300

AT

Pase

,�

-pol

ypep

tide

occi

pita

lh

orn

deve

lopm

ent/

syn

drom

efu

nct

ion

AT

RA

taxi

a-te

lan

giec

tasi

aan

d3q

Seck

elsy

ndr

ome

6012

15K

inas

eD

NA

repa

ir:

CN

Sm

ei-4

1(&

)00

0436

7�

300

RA

D3-

rela

ted

deve

lopm

ent/

fun

ctio

nA

TR

X(X

H2,

X-li

nke

dh

elic

ase

2X

q�

-Th

alas

sem

ia/M

R30

0032

Hel

icas

eC

hro

mos

ome

stru

ctur

eX

NP

(&¶

)00

3933

8�

300

XN

P)sy

ndr

ome;

non

spec

ific

and

tran

scri

ptio

nM

R;

oth

ers

regu

lati

onA

VPR

2A

rgin

ine

vaso

pres

sin

Xq

X-li

nke

dn

eph

roge

nic

3048

00R

ecep

tor

Sign

alin

gpa

thw

ayC

G61

11,

oth

ers

(*)

0039

396

�30

rece

ptor

2di

abet

esin

sipi

dus

(GPC

R):

MR

2sy

stem

icto

xici

tyB

4GA

LT

1�

-1,4

-9p

Con

gen

ital

diso

rder

of13

7060

Tra

nsf

eras

ePr

otei

nm

odifi

cati

onB

cDN

A:G

H13

356,

0027

538

�60

Gal

acto

sylt

ran

sfer

ase

1gl

ycos

ylat

ion

type

IId

(gly

cosy

lati

on):

CN

SC

G14

517

deve

lopm

ent/

fun

ctio

nB

4GA

LT

7�

-1,4

-5q

Eh

lers

-Dan

los

syn

drom

e,60

4327

Tra

nsf

eras

ePr

otei

nm

odifi

cati

onC

G11

780

(&)

0039

258

�73

(XG

PT1)

Gal

acto

sylt

ran

sfer

ase

7pr

oger

oid

form

(gly

cosy

lati

on):

?CN

Sde

velo

pmen

t/fu

nct

ion

BB

S1B

arde

t-Bie

dlsy

ndr

ome

111

qB

arde

t-Bie

dlsy

ndr

ome

120

9901

Un

know

nU

nkn

own

CG

1482

500

3574

1�

62fu

nct

ion

BB

S2B

arde

t-Bie

dlsy

ndr

ome

216

qB

arde

t-Bie

dlsy

ndr

ome

260

6151

Un

know

nU

nkn

own

Non

e—

—fu

nct

ion

(con

tinue

d)


AP

PE

ND

IX

(Con

tinu

ed)

Mol

ecul

ar-

Gen

eC

hr.

OM

IMfu

nct

ion

GO

Dro

soph

ilaFl

yBas

eB

LA

STP

sym

bola

Gen

en

ame

arm

bC

linic

aldi

sord

erc

no.

cate

gory

dB

iolo

gica

lfu

nct

ion

(s)e

hom

olog

(s)f

no.

gE

-val

ueh

BB

S4B

arde

t-Bie

dlsy

ndr

ome

415

qB

arde

t-Bie

dlsy

ndr

ome

460

0374

[Tra

nsf

eras

e]?P

rote

inC

G13

232

(&)

0033

578

�54

mod

ifica

tion

(gly

cosy

lati

on):

MR

caus

eun

know

nB

BS6

Bar

det-B

iedl

syn

drom

e6

20p

Bar

det-B

iedl

syn

drom

e6

6048

96C

hap

eron

ePr

otei

nm

odifi

cati

onT

cp1-

like,

Cct

�(*

)00

0367

6�

11(M

KK

S)(f

oldi

ng)

:M

Rca

use

unkn

own

BC

KD

HA

Bra

nch

ed-c

hai

nke

toac

id19

qM

aple

syru

pur

ine

2486

00O

xido

redu

ctas

eM

etab

olic

(am

ino

acid

):C

G81

99(&

)00

3770

9�

136

deh

ydro

gen

ase

E1�

dise

ase

type

IAM

R2

syst

emic

and

loca

lto

xici

tyB

CK

DH

BB

ran

ched

-ch

ain

keto

acid

6pM

aple

syru

pur

ine

2486

11O

xido

redu

ctas

eM

etab

olic

(am

ino

acid

):C

G17

691

(&)

0039

993

�12

4de

hyd

roge

nas

eE

1�di

seas

ety

peIB

MR

2sy

stem

ican

dlo

cal

toxi

city

BC

S1L

Yeas

tB

CS1

hom

olog

-like

2qT

ubul

opat

hy,

6036

47[N

ucle

otid

eM

etab

olic

(oxi

dati

veC

G49

08(&

)00

3219

5�

146

ence

phal

opat

hy,

and

bin

din

g]ph

osph

oryl

atio

n):

MR

liver

failu

re2

loca

len

ergy

defi

cien

cyB

SCL

2Se

ipin

11q

Ber

ardi

nel

li-Se

ipco

n-

6061

58U

nkn

own

?CN

Sde

velo

pmen

t/EG

:BA

CR

7C10

.100

4033

6�

45ge

nit

allip

odys

trop

hy

fun

ctio

nfu

nct

ion

:h

ypot

hal

amic

-pi

tuit

ary

axis

BSN

DB

artt

in1p

Bar

tter

syn

drom

ew

ith

6064

12T

ran

spor

ter

MR

caus

eun

know

n:

Non

e—

—se

nso

rin

eura

ldea

fnes

s?s

yste

mic

toxi

city

BT

DB

ioti

nid

ase

3pM

ulti

ple

carb

oxyl

ase

2532

60L

igas

eM

etab

olic

(var

ious

):M

Rva

nin-

like,

oth

ers

0040

069

�40

defi

cien

cy2

syst

emic

and

loca

lto

xici

tyC

A2

Car

bon

ican

hyd

rase

II8q

Ost

eope

tros

isw

ith

ren

al25

9730

Lya

seC

NS

deve

lopm

ent/

Car

boni

c00

2784

4�

59tu

bula

rac

idos

isfu

nct

ion

:C

SF,

anhy

dras

e1,

neu

rotr

ansm

issi

on,

oth

ers

?mye

linat

ion

CB

SC

ysta

thio

nin

e�

-syn

thas

e21

qH

omoc

ysti

nur

ia23

6200

Lya

seM

etab

olic

:C

NS

CG

1753

0031

148

�16

3de

velo

pmen

t/fu

nct

ion

;sy

stem

ican

dlo

cal

toxi

city

CG

I58

Com

para

tive

gen

e3p

Ich

thyo

tic

neu

tral

lipid

6047

80H

ydro

lase

Met

abol

ic(f

atty

acid

):C

G18

8200

3322

6�

81id

enti

fica

tion

58st

orag

edi

seas

e?M

R2

loca

lto

xici

ty

(con

tinue

d)


AP

PE

ND

IX

(Con

tinu

ed)

Mol

ecul

ar-

Gen

eC

hr.

OM

IMfu

nct

ion

GO

Dro

soph

ilaFl

yBas

eB

LA

STP

sym

bola

Gen

en

ame

arm

bC

linic

aldi

sord

erc

no.

cate

gory

dB

iolo

gica

lfu

nct

ion

(s)e

hom

olog

(s)f

no.

gE

-val

ueh

CIA

S1C

ryop

yrin

1qC

hro

nic

neu

rolo

gic

6064

16A

popt

osis

?Sig

nal

ing

path

way

Non

e—

—cu

tan

eous

and

regu

lato

r(u

nkn

own

):im

mun

ear

ticu

lar

syn

drom

ere

spon

se;

?MR

2in

flam

mat

ion

CK

N1

(CSA

)C

ocka

yne

syn

drom

ety

peI

5qC

ocka

yne

syn

drom

e21

6400

Tra

nsc

ript

ion

DN

Are

pair

(tra

n-

[will

die

slow

ly,

0040

066

�14

type

Ifa

ctor

scri

ptio

n-c

oupl

ed):

oth

ers]

CN

Sde

velo

pmen

t/fu

nct

ion

(mye

lin)

CL

CN

KB

Ch

lori

dech

ann

el,

1pB

artt

ersy

ndr

ome

6020

23T

ran

spor

ter

MR

caus

eun

know

n:

CG

3111

6(&

)00

5111

6�

108

kidn

ey,

Bty

peII

I?s

yste

mic

toxi

city

CL

N1

Palm

itoy

l-pro

tein

1pN

euro

nal

cero

id60

0722

Hyd

rola

seL

ysos

omal

path

way

Ppt1

(&)

0030

057

�74

(PPT

1)th

ioes

tera

se1

ipof

usci

nos

is,

(lip

opro

tein

):M

R2

infa

nti

lelo

calt

oxic

ity

(neu

ron

)C

LN

2C

eroi

dlip

ofus

cin

osis

,11

pN

euro

nal

cero

id20

4500

Hyd

rola

seL

ysos

omal

path

way

Non

e—

—n

euro

nal

2lip

ofus

cin

osis

,la

te(p

epti

de):

MR

2lo

cal

infa

nti

leto

xici

ty(n

euro

n)

CL

N3

Cer

oid

lipof

usci

nos

is,

16p

Bat

ten

dise

ase

6070

42U

nkn

own

Lys

osom

alpa

thw

ay:

MR

CG

5582

0036

756

�69

neu

ron

al3

fun

ctio

n2

loca

lto

xici

ty(n

euro

n);

?syn

apti

cfu

nct

ion

CL

N5

Cer

oid

lipof

usci

nos

is,

13q

Neu

ron

alce

roid

2567

31U

nkn

own

Lys

osom

alpa

thw

ay:

MR

Non

e—

—n

euro

nal

5lip

ofus

cin

osis

,la

tefu

nct

ion

2lo

cal

toxi

city

infa

nti

le(n

euro

n)

CL

N6

Cer

oid

lipof

usci

nos

is,

15q

Neu

ron

alce

roid

6067

25U

nkn

own

?Lys

osom

alpa

thw

ay:M

RN

one

——

neu

ron

al6

lipof

usci

nos

is,

late

fun

ctio

n2

loca

lto

xici

tyin

fan

tile

(neu

ron

)C

LN

8C

eroi

dlip

ofus

cin

osis

,8p

Prog

ress

ive

epile

psy

6001

43U

nkn

own

?Lys

osom

alpa

thw

ay:M

RN

one

——

neu

ron

al8

wit

hM

Rfu

nct

ion

2lo

cal

toxi

city

(neu

ron

)C

OX

10C

ytoc

hro

me

cox

idas

e17

pPr

ogre

ssiv

e60

2125

Tra

nsf

eras

eM

etab

olic

(oxi

dati

veC

G50

3700

3222

2�

80su

bun

it10

mit

och

ondr

ial

phos

phor

ylat

ion

):M

Ren

ceph

alop

ath

y2

loca

len

ergy

defi

cien

cyC

PS1

Car

bam

oylp

hos

phat

e2q

Hyp

eram

mon

emia

due

2373

00L

igas

eM

etab

olic

(ure

acy

cle)

:ru

dim

enta

ry00

0318

9�

300

syn

thet

ase

1to

CPS

1de

fici

ency

MR

2sy

stem

icto

xici

tyC

REB

BP

CR

EB

-bin

din

gpr

otei

n16

pR

ubin

stei

n-T

aybi

6001

40T

ran

scri

ptio

nT

ran

scri

ptio

nne

jire

(&¶

)00

1562

4�

300

(CB

P)sy

ndr

ome

regu

lato

rre

gula

tion

:C

NS

deve

lopm

ent/

fun

c-ti

on;

?ch

rom

osom

est

ruct

ure

(con

tinue

d)


AP

PE

ND

IX

(Con

tinu

ed)

Mol

ecul

ar-

Gen

eC

hr.

OM

IMfu

nct

ion

GO

Dro

soph

ilaFl

yBas

eB

LA

STP

sym

bola

Gen

en

ame

arm

bC

linic

aldi

sord

erc

no.

cate

gory

dB

iolo

gica

lfu

nct

ion

(s)e

hom

olog

(s)f

no.

gE

-val

ueh

CX

OR

F5C

hro

mos

ome

XX

pO

ral-f

acia

l-dig

ital

3001

70[P

rote

inC

NS

deve

lopm

ent/

Non

e—

—op

enre

adin

gfr

ame

5sy

ndr

ome

type

Ibi

ndi

ng]

fun

ctio

n:

neu

ron

alm

igra

tion

/di

ffer

enti

atio

n(?

mic

rotu

bule

)C

YP27

A1

Cyt

och

rom

eP4

5027

A1

2qC

ereb

rote

ndi

nou

s60

6530

Oxi

dore

duct

ase

Met

abol

ic(l

ipid

):M

R2

Cyp

49a1

,ot

her

s00

3352

4�

42(s

tero

l27

-hyd

roxy

lase

)xa

nth

omat

osis

syst

emic

and

loca

lto

xici

tyD

BT

Dih

ydro

lipoa

mid

e1p

Map

lesy

rup

urin

e24

8610

Tra

nsf

eras

eM

etab

olic

(am

ino

acid

):C

G55

99(&

)00

3061

2�

115

bran

ched

-ch

ain

dise

ase

type

IIM

R2

syst

emic

and

tran

sacy

lase

loca

lto

xici

tyD

CX

Dou

blec

orti

nX

qL

isse

nce

phal

y;30

0121

Prot

ein

bin

din

gC

ytos

kele

ton

CG

1752

8(&

¶)

0032

999

�47

subc

orti

cal

lam

inar

(mic

rotu

bule

):h

eter

otop

ian

euro

nal

mig

rati

onan

ddi

ffer

enti

atio

nD

HC

R7

7-D

ehyd

roch

oles

tero

l11

qSm

ith

-Lem

li-O

pitz

6028

58O

xido

redu

ctas

eM

etab

olic

(ch

oles

tero

l):

Non

e—

—re

duct

ase

syn

drom

ety

pes

I,II

sign

alin

gpa

thw

ay(H

h):

CN

Sde

velo

pmen

t/fu

nct

ion

DIA

1D

iaph

oras

e(N

AD

H-

22q

Met

hem

oglo

bin

emia

2508

00O

xido

redu

ctas

eM

etab

olic

(lip

id):

CN

SC

G59

4600

3621

1�

92cy

toch

rom

eb5

type

IIde

velo

pmen

tan

dre

duct

ase)

fun

ctio

nD

KC

1D

yske

rin

Xq

Dys

kera

tosi

sco

nge

nit

a;30

0126

RN

Abi

ndi

ng

RN

Apr

oces

sin

g(r

RN

A):

Nuc

leol

arpr

otei

nat

0023

184

�17

4H

oyer

aal-

CN

Sde

velo

pmen

t/60

B(¶

)H

reid

arss

onsy

ndr

ome

fun

ctio

n;

?ch

rom

osom

est

ruct

ure

DL

DD

ihyd

rolip

oam

ide

7qM

aple

syru

pur

ine

2469

00O

xido

redu

ctas

eM

etab

olic

(gly

coly

sis)

:C

G74

30(&

)00

3676

2�

300

deh

ydro

gen

ase

dise

ase

type

III

MR

2lo

cal

ener

gyde

fici

ency

DM

1D

ystr

oph

iam

yoto

nic

a19

qC

onge

nit

alm

yoto

nic

6053

77K

inas

e?C

NS

deve

lopm

ent/

[gen

ghis

khan

,00

2308

1�

119

prot

ein

kin

ase

dyst

roph

y1

fun

ctio

n;

nei

ghbo

rin

got

her

s]ge

nes

may

con

trib

ute

toph

enot

ype

DM

DD

ystr

oph

inX

pD

uch

enn

e,B

ecke

r30

0377

Stru

ctur

alC

ytos

kele

ton

(act

in):

dyst

roph

in(&

¶)

0024

242

�30

0m

uscu

lar

dyst

roph

ies

mol

ecul

eC

NS

deve

lopm

ent/

fun

ctio

n(n

euro

ns,

glia

,bl

ood

vess

el)

(con

tinue

d)


AP

PE

ND

IX

(Con

tinu

ed)

Mol

ecul

ar-

Gen

eC

hr.

OM

IMfu

nct

ion

GO

Dro

soph

ilaFl

yBas

eB

LA

STP

sym

bola

Gen

en

ame

arm

bC

linic

aldi

sord

erc

no.

cate

gory

dB

iolo

gica

lfu

nct

ion

(s)e

hom

olog

(s)f

no.

gE

-val

ueh

DN

MT

3BD

NA

met

hyl

tran

sfer

ase

20q

Imm

unod

efici

ency

,60

2900

Tra

nsf

eras

eC

hro

mos

ome

stru

ctur

e:N

one

——

3Bce

ntr

omer

icin

stab

ility

MR

caus

eun

know

nsy

ndr

ome

DPA

GT

1G

lcN

Ac

1-P

tran

sfer

ase

11q

Con

gen

ital

diso

rder

of19

1350

Tra

nsf

eras

ePr

otei

nm

odifi

cati

onC

G52

8700

3247

7�

97gl

ycos

ylat

ion

type

Ij(g

lyco

syla

tion

):C

NS

deve

lopm

ent/

fun

ctio

nD

PM1

Dol

ich

yl-p

hos

phat

e20

qC

onge

nit

aldi

sord

erof

6035

03T

ran

sfer

ase

Prot

ein

mod

ifica

tion

CG

1016

6(&

)00

3279

9�

106

man

nos

yltr

ansf

eras

e1

glyc

osyl

atio

nty

peIe

(gly

cosy

lati

on):

CN

Sde

velo

pmen

t/fu

nct

ion

DPY

DD

ihyd

ropy

rim

idin

e1p

Dih

ydro

pyri

mid

inur

ia27

4270

Oxi

dore

duct

ase

Met

abol

ic(p

yrim

idin

e):

Rhy

thm

ical

ly00

1671

8�

300

deh

ydro

gen

ase

due

toD

PYD

?MR

2n

euro

toxi

city

expr

esse

dde

fici

ency

gene

3(&

)D

PYS

(DH

P)D

ihyd

ropy

rim

idin

ase

8qD

ihyd

ropy

rim

idin

uria

2227

48H

ydro

lase

Met

abol

ic(p

yrim

idin

e):

colla

psin

resp

onse

0023

023

�14

1du

eto

DPY

Sde

fici

ency

?MR

2n

euro

toxi

city

med

iato

rpr

otei

nD

RPL

AA

trop

hin

-112

pPr

ogre

ssiv

em

yocl

onus

1253

70Pr

otei

nbi

ndi

ng

Tra

nsc

ript

ion

regu

lati

onN

one

(see

——

epile

psy

syn

drom

e(n

euro

n)

mat

eria

lsan

dm

eth

od

s)D

UO

X2

Dua

lox

idas

e2

15q

Con

gen

ital

6067

59O

xido

redu

ctas

eH

orm

one

syn

thes

is:

CG

3131

(&)

0031

464

�30

0(T

HO

X2)

hyp

oth

yroi

dism

endo

crin

efu

nct

ion

(th

yroi

d):

CN

Sde

velo

pmen

t/fu

nct

ion

EIF2

AK

3E

ukar

yoti

ctr

ansl

atio

n2p

Wol

cott

-Ral

lison

6040

32K

inas

eT

ran

slat

ion

:C

NS

EIF2

-like

(&)

0037

327

�44

(PEK

)in

itia

tion

fact

or2�

syn

drom

ede

velo

pmen

t/ki

nas

e3

fun

ctio

nEM

X2

Hom

olog

2of

Dro

soph

ila10

qSc

hiz

ence

phal

y60

0035

Tra

nsc

ript

ion

Tra

nsc

ript

ion

empt

ysp

irac

les,

E500

0057

6�

25em

pty

spir

acle

sfa

ctor

regu

lati

on:

CN

Sde

velo

pmen

t/fu

nct

ion

(neu

ron

)ER

CC

2X

erod

erm

api

gmen

tosu

m19

qT

rich

oth

iody

stro

phy;

1263

40Pr

otei

nbi

ndi

ng

Tra

nsc

ript

ion

(bas

al):

Xer

oder

ma

0015

844

�30

0(X

PD)

type

DX

PD/C

ocka

yne

CN

Sde

velo

pmen

t/pi

gmen

tosu

msy

ndr

ome

fun

ctio

n(n

euro

n,

D(&

)gl

ia)

ERC

C3

Xer

oder

ma

pigm

ento

sum

2qX

PB/C

ocka

yne

1335

10H

elic

ase

Tra

nsc

ript

ion

/DN

Aha

ywir

e00

0117

9�

300

(XPB

)ty

peB

syn

drom

ere

pair

:C

NS

deve

lopm

ent/

fun

ctio

n

(con

tinue

d)


AP

PE

ND

IX

(Con

tinu

ed)

Mol

ecul

ar-

Gen

eC

hr.

OM

IMfu

nct

ion

GO

Dro

soph

ilaFl

yBas

eB

LA

STP

sym

bola

Gen

en

ame

arm

bC

linic

aldi

sord

erc

no.

cate

gory

dB

iolo

gica

lfu

nct

ion

(s)e

hom

olog

(s)f

no.

gE

-val

ueh

ERC

C5

Xer

oder

ma

pigm

ento

sum

13q

XPG

/Coc

kayn

e13

3530

Hyd

rola

se?,

DN

Are

pair

mut

agen

-sens

itive

0002

887

�64

(XPG

)ty

peG

syn

drom

eot

her

?(t

ran

scri

ptio

n-

201

(&)

coup

led)

:C

NS

deve

lopm

ent/

fun

ctio

nER

CC

6E

xcis

ion

repa

ircr

oss-

10q

Coc

kayn

esy

ndr

ome

type

1335

40H

ydro

lase

DN

Are

pair

(tra

nsc

rip-

[Hel

icas

e89

B,

0022

787

�79

(CSB

)co

mpl

emen

tin

g6

II;

cere

broo

culo

faci

o-ti

onco

uple

d),

oth

ers]

skel

etal

syn

drom

etr

ansc

ript

ion

:C

NS

deve

lopm

ent/

fun

ctio

nFA

CL

4Fa

tty

acid

CoA

ligas

e,X

qM

RX

63,

MR

X68

3001

57L

igas

eL

ipid

syn

thes

is:

CN

Sl(

2)44

DEa

(&)

0010

609

�17

7lo

ng-

chai

n4

deve

lopm

ent/

fun

ctio

n(n

euro

n)

FAN

CA

Fan

con

ian

emia

16q

Fan

con

ian

emia

2276

50[P

rote

inD

NA

repa

ir:

?CN

SN

one

——

com

plem

enta

tion

com

plem

enta

tion

bin

din

g]de

velo

pmen

t/gr

oup

Agr

oup

Afu

nct

ion

FAN

CC

Fan

con

ian

emia

9qFa

nco

ni

anem

ia22

7645

[Pro

tein

DN

Are

pair

:?C

NS

Non

e—

—co

mpl

emen

tati

onco

mpl

emen

tati

onbi

ndi

ng]

deve

lopm

ent/

grou

pC

grou

pC

fun

ctio

nFB

N1

Fibr

illin

115

qSh

prin

tzen

-Gol

dber

g13

4797

Stru

ctur

alE

xtra

cellu

lar

mat

rix

dum

py(&

)00

0048

8�

50cr

anio

syn

osto

sis

mol

ecul

e(m

icro

fibr

ils):

MR

syn

drom

eca

use

unkn

own

FCM

DFu

kuti

n9q

Fuku

yam

aco

nge

nit

al25

3800

[Tra

nsf

eras

e]Pr

otei

nm

odifi

cati

onN

one

——

mus

cula

rdy

stro

phy

(gly

cosy

lati

on):

CN

Sde

velo

pmen

t(n

euro

nm

igra

tion

,gl

ia)

FGD

1Fa

ciog

enit

aldy

spla

sia

1X

pN

onsp

ecifi

cM

R;

3054

00R

ecep

tor

Sign

alin

gpa

thw

ayC

G20

08,

oth

ers

0037

287

�23

Aar

skog

-Sco

ttsi

gnal

ing

(ph

osph

oin

osit

ide,

syn

drom

epr

otei

nR

ho-

type

Gpr

otei

n)

FGFR

1Fi

brob

last

grow

thfa

ctor

8pC

ran

iosy

nos

tosi

s;A

pert

1363

50R

ecep

tor

Sign

alin

gpa

thw

ayhe

artle

ss,

brea

th-

0010

389

�12

3re

cept

or1

syn

drom

e;ot

her

s(r

ecep

tor

tyro

sin

ele

ss(¶

)ki

nas

e):

?CN

Sde

velo

pmen

t/fu

nct

ion

FGFR

2Fi

brob

last

grow

thfa

ctor

10q

Ape

rtan

dot

her

cran

io-

1769

43R

ecep

tor

Sign

alin

gpa

thw

aybr

eath

less

,he

art-

0005

592

�13

0re

cept

or2

syn

osto

sis

syn

drom

es(r

ecep

tor

tyro

sin

ele

ss(¶

)ki

nas

e):

CN

Sde

velo

pmen

t/fu

nct

ion

(con

tinue

d)


AP

PE

ND

IX

(Con

tinu

ed)

Mol

ecul

ar-

Gen

eC

hr.

OM

IMfu

nct

ion

GO

Dro

soph

ilaFl

yBas

eB

LA

STP

sym

bola

Gen

en

ame

arm

bC

linic

aldi

sord

erc

no.

cate

gory

dB

iolo

gica

lfu

nct

ion

(s)e

hom

olog

(s)f

no.

gE

-val

ueh

FGFR

3Fi

brob

last

grow

thfa

ctor

4pC

ran

iosy

nos

tose

s,13

4934

Rec

epto

rSi

gnal

ing

path

way

hear

tless

,br

eath

-00

1038

9�

127

rece

ptor

3ch

ondr

odys

plas

ias

(rec

epto

rty

rosi

ne

less

(¶)

kin

ase)

:?C

NS

deve

lopm

ent/

fun

ctio

nFH

Fum

arat

eh

ydra

tase

1qFu

mar

icac

idur

iadu

eto

1368

50L

yase

Met

abol

ic(c

itri

cac

idC

G40

94,

oth

ers

0029

889

�30

0FH

defi

cien

cycy

cle)

:C

NS

deve

lopm

ent/

fun

ctio

n(?

neu

ron

alm

igra

tion

)FK

RP

Fuku

tin

-rel

ated

prot

ein

19q

Mus

cula

rdy

stro

phy

wit

h60

6596

Un

know

n?P

rote

inm

odifi

cati

onC

G15

651

0034

567

�33

MR

and

cere

bella

rfu

nct

ion

(gly

cosy

lati

on):

CN

Scy

sts

deve

lopm

ent/

fun

ctio

nFL

J901

30D

ymec

lin18

qD

yggv

e-M

elch

ior-

2238

00U

nkn

own

?Pro

tein

mod

ifica

tion

BcD

NA

:GH

0253

600

2760

7�

127

Cla

usen

dise

ase

fun

ctio

n(p

rote

ogly

can

):M

Rca

use

unkn

own

FLN

AFi

lam

inA

Xq

Peri

ven

tric

ular

nod

ular

3000

17Pr

otei

nbi

ndi

ng

Cyt

oske

leto

n(a

ctin

):ch

eeri

o(&

¶)

0014

141

�30

0h

eter

otop

ia;

oth

ers

CN

Sde

velo

pmen

t/fu

nct

ion

(neu

ron

alm

igra

tion

)FM

R1

Frag

ileX

men

tal

Xq

Frag

ileX

men

tal

3095

50R

NA

bin

din

gT

ran

slat

ion

regu

lati

on:

dfm

r1(¶

)00

2873

4�

95re

tard

atio

n1

reta

rdat

ion

CN

Sde

velo

pmen

t/sy

ndr

ome

fun

ctio

n(?

neu

ron

aldi

ffer

enti

atio

n)

FMR

2Fr

agile

site

men

tal

Xq

X-li

nke

dn

onsp

ecifi

cM

R30

9548

[Tra

nsc

ript

ion

Tra

nsc

ript

ion

lillip

utia

n(*

)00

4111

1�

19re

tard

atio

n2

regu

lato

r]re

gula

tion

:C

NS

deve

lopm

ent/

fun

ctio

n(?

neu

ron

aldi

ffer

enti

atio

n)

FOX

P2••

•Fo

rkh

ead

box

P27q

Dev

elop

men

tal

verb

al60

5317

Tra

nsc

ript

ion

Tra

nsc

ript

ion

CG

1689

9(&

¶)

0037

735

�32

dysp

raxi

are

gula

tor

regu

lati

on:

CN

Sde

velo

pmen

t/fu

nct

ion

FRA

S1Fr

aser

syn

drom

ege

ne

14q

Fras

ersy

ndr

ome

6078

30U

nkn

own

?Ext

race

llula

rm

atri

x:[f

ur2,

oth

ers]

0004

598

�65

fun

ctio

nC

NS

deve

lopm

ent/

fun

ctio

n

(con

tinue

d)


AP

PE

ND

IX

(Con

tinu

ed)

Mol

ecul

ar-

Gen

eC

hr.

OM

IMfu

nct

ion

GO

Dro

soph

ilaFl

yBas

eB

LA

STP

sym

bola

Gen

en

ame

arm

bC

linic

aldi

sord

erc

no.

cate

gory

dB

iolo

gica

lfu

nct

ion

(s)e

hom

olog

(s)f

no.

gE

-val

ueh

FUC

A1

�-l

-Fuc

osid

ase

11p

Fuco

sido

sis

2300

00H

ydro

lase

Lys

osom

alpa

thw

ayC

G61

2800

3616

9�

129

(gly

copr

otei

n):

MR

2lo

cal

toxi

city

(neu

ron

,gl

ia)

FUC

T1

GD

P-fu

cose

tran

spor

ter

111

pC

onge

nit

aldi

sord

erof

6058

81T

ran

spor

ter

Prot

ein

mod

ifica

tion

CG

9620

0037

567

�76

glyc

osyl

atio

nty

peII

c(g

lyco

syla

tion

):C

NS

deve

lopm

ent/

fun

ctio

nG

6PD

Glu

cose

-6-p

hos

phat

eX

qN

onsp

her

ocyt

ic30

5900

Oxi

dore

duct

ase

Met

abol

ic(g

lyco

lysi

s):

Zwis

chen

ferm

ent

0004

057

�30

0de

hyd

roge

nas

eh

emol

ytic

anem

ia;

MR

2sy

stem

icto

xici

ty(&

)ke

rnic

teru

sG

AL

EG

alac

tose

epim

eras

e1p

Epi

mer

ase-

defi

cien

cy60

6953

Isom

eras

eM

etab

olic

CG

1203

0(&

)00

3514

7�

124

gala

ctos

emia

(car

boh

ydra

te):

?CN

Sde

velo

pmen

t/fu

nct

ion

GA

LT

Gal

acto

se-1

-ph

osph

ate

9pT

ran

sfer

ase-

defi

cien

cy60

6999

Tra

nsf

eras

eM

etab

olic

CG

9232

0031

845

�11

8ur

idyl

yltr

ansf

eras

ega

lact

osem

ia(c

arbo

hyd

rate

):M

R2

loca

lto

xici

tyG

AM

TG

uan

idin

oace

tate

19p

Rev

ersi

ble

brai

ncr

eati

ne

6012

40T

ran

sfer

ase

Met

abol

ic(c

reat

ine)

:N

one

——

met

hyl

tran

sfer

ase

defi

cien

cyC

NS

deve

lopm

ent/

fun

ctio

n;

MR

2sy

stem

icen

ergy

defi

cien

cyG

AT

Ml-

Arg

inin

e:gl

ycin

e15

qIn

born

erro

rof

crea

tin

e60

2360

Tra

nsf

eras

eM

etab

olic

(cre

atin

e):

Non

e—

—(A

GA

T)

amid

inot

ran

sfer

ase

met

abol

ism

CN

Sde

velo

pmen

t/fu

nct

ion

;M

R2

syst

emic

ener

gyde

fici

ency

GC

DH

•••

Glu

tary

l-CoA

19p

Glu

tari

caci

dem

iaI

2316

70O

xido

redu

ctas

eM

etab

olic

(am

ino

acid

):C

G95

47(&

)00

3182

4�

163

deh

ydro

gen

ase

CN

Sde

velo

pmen

t/fu

nct

ion

;?n

euro

toxi

city

GC

H1

GT

Pcy

cloh

ydro

lase

114

qA

typi

cal

hyp

er-

6002

25H

ydro

lase

Met

abol

ic(B

H4

syn

the-

Punc

h00

0316

2�

75ph

enyl

alan

inem

iasi

s):

neu

rotr

ansm

is-

sion

(am

ines

);sy

stem

icto

xici

tyG

CS1

Glu

cosi

dase

I2p

Con

gen

ital

diso

rder

of60

1336

Hyd

rola

sePr

otei

nm

odifi

cati

onC

G15

9700

3028

9�

138

glyc

osyl

atio

nty

peII

b(g

lyco

syla

tion

):C

NS

deve

lopm

ent/

fun

ctio

n

(con

tinue

d)


AP

PE

ND

IX

(Con

tinu

ed)

Mol

ecul

ar-

Gen

eC

hr.

OM

IMfu

nct

ion

GO

Dro

soph

ilaFl

yBas

eB

LA

STP

sym

bola

Gen

en

ame

arm

bC

linic

aldi

sord

erc

no.

cate

gory

dB

iolo

gica

lfu

nct

ion

(s)e

hom

olog

(s)f

no.

gE

-val

ueh

GC

SHG

lyci

ne

clea

vage

syst

em16

qG

lyci

ne

ence

phal

opat

hy

2383

30T

ran

sfer

ase

Met

abol

ic(a

min

oac

id):

pum

ples

s00

2794

5�

26H

prot

ein

MR

2n

euro

/glia

lto

xici

ty(n

euro

-tr

ansm

issi

on)

GD

I1G

uan

ine

diss

ocia

tion

Xq

MR

X41

,M

RX

4830

0104

Rec

epto

rsi

gnal

-Si

gnal

ing

path

way

(sm

all

GD

Pdi

ssoc

iatio

n00

0486

8�

156

inh

ibit

or1

(Rab

GD

I�)

ing

prot

ein

G):

neu

ron

alde

velo

p-in

hibi

tor

(&¶

)m

ent/

fun

ctio

n(n

euro

tran

smis

sion

)G

FAP

Glia

lfi

brill

ary

acid

ic17

qA

lexa

nde

rdi

seas

e13

7780

Stru

ctur

alC

ytos

kele

ton

(in

term

e-[L

amin

,Lam

inC

]00

0252

5�

40pr

otei

nm

olec

ule

diat

efi

lam

ent)

:gl

ial

deve

lopm

ent/

fun

ctio

n(a

stro

cyte

)G

KG

lyce

rol

kin

ase

Xp

Hyp

ergl

ycer

olem

iadu

e30

7030

Kin

ase

Met

abol

ic(g

luco

neo

-G

lyce

rol

kina

se,

0025

592

�15

5to

GK

defi

cien

cyge

nes

is):

?MR

2lo

cal/

oth

ers

syst

emic

ener

gyde

fici

ency

GL

B1

�-G

alac

tosi

dase

13p

GM

1-ga

ngl

iosi

dosi

s23

0500

Hyd

rola

seL

ysos

omal

path

way

CG

3132

,C

G90

9200

3797

7�

139

type

sI,

II(g

lyco

lipid

):M

R2

loca

ltox

icit

y(n

euro

n)

GL

DC

Gly

cin

ede

carb

oxyl

ase

9pG

lyci

ne

ence

phal

opat

hy

2383

00O

xido

redu

ctas

eM

etab

olic

(am

ino

acid

):C

G39

9900

3780

1�

300

MR

2n

euro

/glia

lto

xici

ty(n

euro

tran

smis

sion

)G

LI3

GL

I-K

rupp

elfa

mily

7pA

croc

allo

sal

syn

drom

e;16

5240

Tra

nsc

ript

ion

Tra

nsc

ript

ion

regu

la-

cubi

tus

inte

rrup

tus

0004

859

�93

mem

ber

3G

reig

ceph

alop

oly-

fact

orti

on:

CN

Sde

velo

p-(&

¶)

syn

dact

yly

men

t/fu

nct

ion

(neu

-ro

nal

diff

eren

tiat

ion

)G

M2A

Gan

glio

side

5qT

ay-S

ach

sdi

seas

e,27

2750

En

zym

eL

ysos

omal

path

way

(gly

-N

one

——

GM

2-ac

tiva

tor

AB

vari

ant

regu

lato

rco

lipid

):M

R2

loca

lto

xici

ty(n

euro

n,

glia

)G

NA

SSt

imul

ator

yG

prot

ein

,20

qA

lbri

ght

her

edit

ary

1393

20N

ucle

otid

eSi

gnal

ing

path

way

Gpr

otei

ns�

60A

0001

123

�16

3�

-sub

unit

oste

odys

trop

hy

bin

din

g(G

PCR

→cA

MP)

:(&

¶)

CN

Sfu

nct

ion

(?n

euro

nal

plas

tici

ty)

GN

PAT

Gly

cero

nep

hos

phat

e1q

Rh

izom

elic

6027

44T

ran

sfer

ase

Lip

idsy

nth

esis

:C

NS

de-

Dha

p-at

(&)

0040

212

�74

O-a

cylt

ran

sfer

ase

chon

drod

yspl

asia

velo

pmen

t/fu

nct

ion

pun

ctat

aty

peII

(glia

:m

yelin

)G

NS

(G6S

)N

-Ace

tylg

luco

sam

ine-

6-12

qM

ucop

olys

acch

arid

osis

6076

64H

ydro

lase

Lys

osom

alpa

thw

ayC

G18

278

(&)

0033

836

�11

0su

lfat

ase

IIID

(San

filli

po(g

lyco

sam

inog

lyca

n):

syn

drom

eD

)M

R2

loca

lto

xici

ty

(con

tinue

d)


AP

PE

ND

IX

(Con

tinu

ed)

Mol

ecul

ar-

Gen

eC

hr.

OM

IMfu

nct

ion

GO

Dro

soph

ilaFl

yBas

eB

LA

STP

sym

bola

Gen

en

ame

arm

bC

linic

aldi

sord

erc

no.

cate

gory

dB

iolo

gica

lfu

nct

ion

(s)e

hom

olog

(s)f

no.

gE

-val

ueh

GPC

3G

lypi

can

3X

qSi

mps

on-G

olab

i-Beh

mel

3000

37Si

gnal

Sign

alin

gpa

thw

ays

divi

sion

0011

577

�23

syn

drom

ety

peI

tran

sduc

er(T

GF�

,R

TK

,W

nt)

:ab

norm

ally

?CN

Sde

velo

pmen

t/de

laye

d(&

¶)

fun

ctio

nG

PHG

eph

yrin

14q

Mol

ybde

num

cofa

ctor

6039

30Pr

otei

nbi

ndi

ng

CN

Sde

velo

pmen

t/ci

nnam

on(¶

)00

0031

6�

59de

fici

ency

type

Cfu

nct

ion

:n

euro

tran

smis

sion

and

met

abol

ic(s

eeM

OC

S1,2

)G

PIG

luco

se-6

-ph

osph

ate

iso-

19q

Hem

olyt

ican

emia

due

to17

2400

Isom

eras

eC

NS

deve

lopm

ent/

fun

c-Ph

osph

oglu

cose

0003

074

�30

0m

eras

e(n

euro

leuk

in)

GPI

defi

cien

cyti

on(n

euro

nsu

rviv

al,

isom

eras

e(¶

)di

ffer

enti

atio

n,

?pla

stic

ity)

GSS

Glu

tath

ion

esy

nth

etas

e20

q5-

Oxo

prol

inur

iadu

eto

6010

02L

igas

eM

etab

olic

(gen

eral

cell

CG

3249

5(&

)00

5249

5�

92G

SSde

fici

ency

inte

grit

y):

?MR

2lo

cal/

syst

emic

toxi

city

GU

SB�

-Glu

curo

nid

ase

7qM

ucop

olys

acch

arid

osis

2532

20H

ydro

lase

Lys

osom

alpa

thw

ayC

G15

117,

0034

417

�14

6ty

peV

II(S

ly(g

lyco

sam

inog

lyca

n):

CG

2135

syn

drom

e)M

R2

loca

lto

xici

tyH

ESX

1H

omeo

box

gen

e3p

Sept

oopt

icdy

spla

sia

6018

02T

ran

scri

ptio

nT

ran

scri

ptio

nre

gula

-[P

HD

P,ot

her

s]00

2533

4�

14ex

pres

sed

inE

Sce

llsfa

ctor

tion

:C

NS

and

endo

-cr

ine

(pit

uita

ry)

deve

l-op

men

t/fu

nct

ion

HEX

A••

•H

exos

amin

idas

eA

15q

Tay

-Sac

hs

dise

ase

6068

69H

ydro

lase

Lys

osom

alpa

thw

ayH

exo2

,ot

her

s00

4162

9�

62(g

lyco

lipid

):M

R2

loca

ltox

icit

y(n

euro

n)

HEX

BH

exos

amin

idas

eB

5qSa

ndh

off

dise

ase

6068

73H

ydro

lase

Lys

osom

alpa

thw

ayH

exo2

,ot

her

s00

4162

9�

64(G

M2-

gan

glio

sido

sis)

(gly

colip

id):

MR

2lo

calt

oxic

ity

(neu

ron

)H

LC

SH

oloc

arbo

xyla

se21

qB

ioti

n-r

espo

nsi

vem

ulti

-25

3270

Lig

ase

Met

abol

ic(v

ario

us):

MR

CG

1467

000

3733

2�

67sy

nth

etas

epl

eca

rbox

ylas

e2

syst

emic

and

loca

lde

fici

ency

toxi

city

(see

also

PC,

PCC

)H

MG

CL

3-H

ydro

xy-3

-1p

3-H

ydro

xy-3

-24

6450

Lya

seM

etab

olic

(var

ious

):sy

s-C

G10

399

0031

877

�99

met

hyl

glut

aryl

-CoA

met

hyl

glut

aric

tem

icn

euro

toxi

city

;ly

ase

acid

uria

glia

lde

velo

pmen

t/fu

nct

ion

(mye

lin)

HPD

4-H

ydro

xyph

enyl

-12

qT

yros

inem

iaty

peII

I27

6710

Oxi

dore

duct

ase

Met

abol

ic(a

min

oac

id):

CG

1179

600

3699

2�

140

pyru

vate

diox

ygen

ase

?MR

2sy

stem

icto

xici

ty

(con

tinue

d)


AP

PE

ND

IX

(Con

tinu

ed)

Mol

ecul

ar-

Gen

eC

hr.

OM

IMfu

nct

ion

GO

Dro

soph

ilaFl

yBas

eB

LA

STP

sym

bola

Gen

en

ame

arm

bC

linic

aldi

sord

erc

no.

cate

gory

dB

iolo

gica

lfu

nct

ion

(s)e

hom

olog

(s)f

no.

gE

-val

ueh

HPR

TH

ypox

anth

ine

phos

pho-

Xq

Les

ch-N

yhan

syn

drom

e30

8000

Tra

nsf

eras

eM

etab

olic

(pur

ine)

:N

one

——

ribo

sylt

ran

sfer

ase

?neu

rotr

ansm

issi

on(D

A);

?C

NS

deve

l(n

euro

n)

IDS

Idur

onat

e2-

sulf

atas

eX

qM

ucop

olys

acch

arid

osis

3099

00H

ydro

lase

Lys

osom

alpa

thw

ayC

G12

014

0035

445

�11

8ty

peII

(Hun

ter

(gly

cosa

min

ogly

can

):sy

ndr

ome)

MR

2lo

cal

toxi

city

IDU

A�

-l-I

duro

nid

ase

4pM

ucop

olys

acch

arid

osis

2528

00H

ydro

lase

Lys

osom

alpa

thw

ayC

G62

0100

3234

3�

64ty

peI

(Hur

ler

(gly

cosa

min

ogly

can

):sy

ndr

ome)

MR

2lo

cal

toxi

city

IGF1

Insu

lin-li

kegr

owth

12q

Gro

wth

reta

rdat

ion

wit

h14

7440

Lig

and

Sign

alin

gpa

thw

ayN

one

——

fact

or1

deaf

nes

san

dM

R(R

TK

):C

NS

deve

lop-

men

t/fu

nct

ion

(neu

ron

,gl

ia)

IKB

KG

Inh

ibit

orof

KB

kin

ase,

Xq

Inco

nti

nen

tia

pigm

enti

3002

48Si

gnal

Sign

alin

gpa

thw

ay(m

ul-

Non

e—

—(N

EMO

)�

-sub

unit

type

IItr

ansd

ucer

tipl

e):

?CN

Sde

velo

p-m

ent/

fun

ctio

n(?

cell

surv

ival

)IL

1RA

PL1

Inte

rleu

kin

1re

cept

orX

pM

RX

3430

0206

Sign

alSi

gnal

ing

path

way

(cyt

o-[T

ehao

,ot

her

s]00

2676

0�

13ac

cess

ory

tran

sduc

erki

ne)

:?C

NS

deve

lop-

prot

ein

-like

1m

ent/

fun

ctio

nIT

GA

7In

tegr

in�

-712

qC

onge

nit

alm

yopa

thy

6005

36R

ecep

tor

Sign

alin

gpa

thw

ay(i

n-

mul

tiple

edem

atou

s00

0445

6�

83te

grin

):?C

NS

deve

lop-

win

gs(&

¶)

men

t/fu

nct

ion

JAG

1Ja

gged

120

pA

lagi

llesy

ndr

ome

6019

20L

igan

dSi

gnal

ing

path

way

Serr

ate

(&¶

)00

0419

7�

168

(Not

ch):

CN

Sde

vel-

opm

ent/

fun

ctio

n(n

euro

n,

glia

,?b

lood

vess

el)

KC

NJ1

Pota

ssiu

mch

ann

elJ1

,11

qB

artt

ersy

ndr

ome

type

II,

6003

59T

ran

spor

ter

MR

caus

eun

know

n:

Ir,

Irk2

(*)

0039

061

�76

(RO

MK

)in

war

dly

rect

ifyi

ng

ante

nat

al?s

yste

mic

toxi

city

hyp

erca

lciu

ric

form

KC

NJ1

1Po

tass

ium

chan

nel

J11,

11p

Hyp

erin

sulin

emic

hyp

o-60

0937

Tra

nsp

orte

rE

ndo

crin

e(p

ancr

eas)

:Ir

,Ir

k2(*

)00

3906

1�

86(K

ir6.

2)in

war

dly

rect

ifyi

ng

glyc

emia

ofin

fan

cyM

R2

syst

emic

fuel

defi

cien

cyL

1CA

ML

1ce

llad

hes

ion

mol

ecul

eX

qM

ASA

syn

drom

e;H

SAS;

3088

40C

ell

adh

esio

nC

ell

adh

esio

n:

CN

Sde

-ne

urog

lian

(&¶

)00

0296

8�

136

SPG

1m

olec

ule

velo

pmen

t/fu

nct

ion

(neu

ron

mig

rati

on,

diff

eren

tiat

ion

,?s

urvi

val)

(con

tinue

d)


AP

PE

ND

IX

(Con

tinu

ed)

Mol

ecul

ar-

Gen

eC

hr.

OM

IMfu

nct

ion

GO

Dro

soph

ilaFl

yBas

eB

LA

STP

sym

bola

Gen

en

ame

arm

bC

linic

aldi

sord

erc

no.

cate

gory

dB

iolo

gica

lfu

nct

ion

(s)e

hom

olog

(s)f

no.

gE

-val

ueh

LA

MA

2L

amin

in�

-2(m

eros

in)

6qC

onge

nit

alm

eros

in-

1562

25St

ruct

ural

Ext

race

llula

rm

atri

x:w

ing

blis

ter

(&¶

)00

0400

2�

300

defi

cien

tm

uscu

lar

mol

ecul

eC

NS

deve

lopm

ent/

dyst

roph

yfu

nct

ion

(neu

ron

alm

igra

tion

;m

yelin

)L

AM

P2L

ysos

ome-

asso

ciat

edX

qG

lyco

gen

stor

age

dise

ase

3090

60Pr

otei

nbi

ndi

ng

Lys

osom

alpa

thw

ay:

MR

Non

e—

—m

embr

ane

prot

ein

2II

Bca

use

unkn

own

;?lo

cal

toxi

city

(neu

ron

,gl

ia)

LA

RG

EA

cety

lglu

cosa

min

yltr

ans-

22q

Con

gen

ital

mus

cula

r60

3590

Tra

nsf

eras

ePr

otei

nm

odifi

cati

onC

G32

53,

oth

ers

(*)

0041

706

�19

fera

se-li

kepr

otei

ndy

stro

phy

ID(g

lyco

syla

tion

):C

NS

deve

lopm

ent/

fun

ctio

nL

IS1

Plat

elet

-act

ivat

ing

fact

or17

pL

isse

nce

phal

y;60

1545

Un

clas

sifi

eden

-C

ytos

kele

ton

(mic

ro-

Lis

senc

epha

ly-1

(&¶

)00

1575

4�

300

(PA

FAH

-ac

etyl

hyd

rola

se1B

�su

bcor

tica

lla

min

arzy

me

tubu

le):

CN

Sde

velo

p-1B

1)h

eter

otop

iam

ent/

fun

ctio

n(n

euro

nm

igra

tion

,?p

rolif

erat

ion

)L

RPP

RC

Leu

cin

e-ri

chPP

Rm

otif

-2p

Lei

ghsy

ndr

ome,

Fren

ch-

6075

44[D

NA

bin

din

g]M

etab

olic

(oxi

dati

vebi

coid

stab

ility

0032

679

�79

con

tain

ing

prot

ein

Can

adia

nty

peph

osph

oryl

atio

n):

MR

fact

or(&

)2

loca

len

ergy

defi

cien

cyM

AN

2B1

�-M

ann

osid

ase

2B1,

19q

�-M

ann

osid

osis

2485

00H

ydro

lase

Lys

osom

alpa

thw

ay(g

ly-

BcD

NA

:GH

0241

9,00

2761

1�

300

lyso

som

alco

prot

ein

):M

R2

oth

ers

loca

lto

xici

ty(n

euro

n,

glia

)ve

ssel

MA

NB

A�

-Man

nos

idas

e4q

�-M

ann

osid

osis

2485

10H

ydro

lase

Lys

osom

alpa

thw

ay(g

ly-

CG

1258

200

3721

5�

72co

prot

ein

):M

R2

loca

lto

xici

ty(n

euro

n,

glia

)M

AO

AM

onoa

min

eox

idas

eA

Xp

Bru

nn

ersy

ndr

ome

3098

50O

xido

redu

ctas

eM

etab

olic

(am

ine)

:CN

SN

one

——

deve

lopm

ent/

fun

ctio

n:

neu

rotr

ans-

mis

sion

(DA

,5H

T)

MA

T1A

Met

hio

nin

ead

enos

yl-

10q

Met

hio

nin

ead

enos

yl-

2508

50T

ran

sfer

ase

Met

abol

ic(m

eth

ion

ine)

:M

(2)2

1AB

0005

278

�16

2tr

ansf

eras

etr

ansf

eras

eI/

III

CN

Sde

velo

pmen

t/de

fici

ency

fun

ctio

n(g

lia:m

yelin

)M

CC

C1

3-M

eth

ylcr

oton

yl-C

oA3q

3-M

eth

ylcr

oton

yl-

2102

00L

igas

eM

etab

olic

(am

ino

acid

):C

G21

18(&

)00

3987

7�

300

(MC

CA

)ca

rbox

ylas

e1

glyc

inur

iaI

MR

2lo

cal

and

syst

emic

neu

rogl

ial

toxi

city

(con

tinue

d)


AP

PE

ND

IX

(Con

tinu

ed)

Mol

ecul

ar-

Gen

eC

hr.

OM

IMfu

nct

ion

GO

Dro

soph

ilaFl

yBas

eB

LA

STP

sym

bola

Gen

en

ame

arm

bC

linic

aldi

sord

erc

no.

cate

gory

dB

iolo

gica

lfu

nct

ion

(s)e

hom

olog

(s)f

no.

gE

-val

ueh

MC

CC

23-

Met

hyl

crot

onyl

-CoA

5q3-

Met

hyl

crot

onyl

-21

0210

Lig

ase

Met

abol

ic(a

min

oac

id):

CG

3267

(&)

0042

083

�30

0(M

CC

B)

carb

oxyl

ase

2gl

ycin

uria

IIM

R2

loca

lan

dsy

stem

icn

euro

glia

lto

xici

tyM

CO

LN

1M

ucol

ipin

119

pM

ucol

ipid

osis

IV60

5248

Tra

nsp

orte

rL

ysos

omal

path

way

(gly

-C

G87

4300

3690

4�

100

colip

id):

MR

2lo

cal

toxi

city

(neu

ron

)M

CPH

1M

icro

ceph

alin

8pPr

imar

ym

icro

ceph

aly

160

7117

[DN

Abi

ndi

ng]

(?D

NA

repa

ir):

CN

Sde

-[C

G89

81]

0033

664

�12

velo

pmen

t/fu

nct

ion

:n

euro

gen

esis

MEC

P2M

eth

yl-C

pG-b

indi

ng

Xq

Ret

tsy

ndr

ome;

3000

05D

NA

bin

din

gT

ran

scri

ptio

nre

gula

-N

one

——

prot

ein

2M

RX

16;

neo

nat

alti

on;

CN

Sde

velo

p-en

ceph

alop

ath

y;m

ent/

fun

ctio

n:

neu

-ot

her

ron

diff

eren

tiat

ion

MG

AT

2�

-1,2

-N-A

cety

lglu

cos-

14q

Con

gen

ital

diso

rder

of60

2616

Tra

nsf

eras

ePr

otei

nm

odifi

cati

onM

gat2

0039

738

�57

amin

yltr

ansf

eras

eII

glyc

osyl

atio

nty

peII

a(g

lyco

syla

tion

):C

NS

deve

lopm

ent/

fun

ctio

nM

ID1

Mid

line

1X

pO

pitz

syn

drom

ety

peI

3000

00Pr

otei

nbi

ndi

ng

Cyt

oske

leto

n(m

icro

-C

G31

721

(¶)

0051

721

�30

tubu

le):

CN

Sde

velo

p-m

ent/

fun

ctio

n(?

pro-

lifer

atio

n)

ML

YCD

Mal

onyl

-CoA

16q

ML

YCD

defi

cien

cy60

6761

Lya

seM

etab

olic

(?fa

tty

acid

):n

one

——

deca

rbox

ylas

e?C

NS

deve

lopm

ent/

fun

ctio

nM

OC

S1(o

rfs

Mol

ybde

num

6pM

olyb

den

umco

fact

or60

3707

Un

clas

sifi

edM

etab

olic

(am

ino

acid

sor

fsA

and

B:

0036

122

�12

3,A

,B

)co

fact

orsy

nth

esis

1de

fici

ency

type

Aen

zym

ean

dot

her

s):

MR

2M

ocs1

�32

loca

lto

xici

ty(n

euro

n,

glia

)M

OC

S2M

olyb

dopt

erin

syn

thas

e,5q

Mol

ybde

num

cofa

ctor

6037

08U

ncl

assi

fied

Met

abol

ic(a

min

oac

ids

orfs

Aan

dB

:00

3928

0�

13,

(orf

sA

,B

)sm

alla

nd

larg

esu

bun

its

defi

cien

cyty

peB

enzy

me

and

oth

ers)

:M

R2

CG

1023

8i

�29

loca

lto

xici

ty(n

euro

n,

glia

)M

PDU

1M

ann

ose-

P-do

lich

ol17

pC

onge

nit

aldi

sord

erof

6040

41[C

hap

eron

e]Pr

otei

nm

odifi

cati

onC

G37

9200

3166

2�

45(L

ec35

)ut

iliza

tion

defe

ct1

glyc

osyl

atio

nty

peIf

(gly

cosy

lati

on):

CN

Sde

velo

pmen

t/fu

nct

ion

(con

tinue

d)


AP

PE

ND

IX

(Con

tinu

ed)

Mol

ecul

ar-

Gen

eC

hr.

OM

IMfu

nct

ion

GO

Dro

soph

ilaFl

yBas

eB

LA

STP

sym

bola

Gen

en

ame

arm

bC

linic

aldi

sord

erc

no.

cate

gory

dB

iolo

gica

lfu

nct

ion

(s)e

hom

olog

(s)f

no.

gE

-val

ueh

MT

AT

P6A

TP

syn

thas

esu

bun

it6

Mt

Lei

ghsy

ndr

ome;

5160

60T

ran

spor

ter

Met

abol

ic(o

xida

tive

mt:A

TPa

se6

0013

672

�16

neu

ropa

thy,

atax

ia,

phos

phor

ylat

ion

):M

Rre

tin

itis

pigm

ento

sa2

loca

len

ergy

defi

cien

cyM

TC

O1

Cyt

och

rom

ec

oxid

ase

Mt

Mit

och

ondr

ial

5160

30O

xido

redu

ctas

eM

etab

olic

(oxi

dati

vem

t:CoI

0013

674

�30

0su

bun

itI

syn

drom

icph

osph

oryl

atio

n):

MR

ence

phal

opat

hy

2lo

cal

ener

gyde

fici

ency

MT

CO

2C

ytoc

hro

me

cox

idas

eM

tM

itoc

hon

dria

l51

6040

Oxi

dore

duct

ase

Met

abol

ic(o

xida

tive

mt:C

oII

0013

675

�52

subu

nit

IIen

ceph

alop

ath

yph

osph

oryl

atio

n):

MR

2lo

cal

ener

gyde

fici

ency

MT

CO

3C

ytoc

hro

me

cox

idas

eM

tL

eigh

-like

5160

50O

xido

redu

ctas

eM

etab

olic

(oxi

dati

vem

t:CoI

II00

1367

6�

79su

bun

itII

Ien

ceph

alop

ath

y;ph

osph

oryl

atio

n):

MR

ME

LA

S2

loca

len

ergy

defi

cien

cyM

TC

YBC

ytoc

hro

me

bof

com

plex

Mt

Mul

tisy

stem

mit

och

on-

5160

20O

xido

redu

ctas

eM

etab

olic

(oxi

dati

vem

t:Cyt

-b00

1367

8�

107

III

dria

ldi

sord

erph

osph

oryl

atio

n):

MR

2lo

cal

ener

gyde

fici

ency

MT

HFR

Met

hyl

enet

etra

hyd

ro-

1pH

omoc

ysti

nur

iadu

eto

6070

93O

xido

redu

ctas

eM

etab

olic

(met

hio

nin

e):

CG

7560

0036

157

�21

fola

tere

duct

ase

MT

HFR

defi

cien

cyC

NS

deve

lopm

ent/

fun

ctio

n(m

yelin

)M

TN

D5

NA

DH

-ubi

quin

one

oxid

o-M

tL

eigh

syn

drom

e,M

EL

AS

5160

05O

xido

redu

ctas

eM

etab

olic

(oxi

dati

vem

t:ND

500

1368

4�

65re

duct

ase

subu

nit

5sy

ndr

ome

phos

phor

ylat

ion

):M

R2

loca

len

ergy

defi

cien

cyM

TR

Met

hio

nin

esy

nth

ase

1qM

eth

ylco

bala

min

defi

-15

6570

Tra

nsf

eras

eM

etab

olic

(met

hio

nin

e):

Non

e—

—ci

ency

,cb

lGty

peC

NS

deve

lopm

ent/

fun

ctio

n(m

yelin

)M

TR

RM

eth

ion

ine

syn

thas

e5p

Hom

ocys

tin

uria

-60

2568

Tra

nsf

eras

eM

etab

olic

(met

hio

nin

e):

[Cpr

,ot

her

s]00

1562

3�

46re

duct

ase

meg

alob

last

ican

emia

CN

Sde

velo

pmen

t/fu

nct

ion

(mye

lin)

MT

TE

Mit

och

ondr

ial

glut

amic

Mt

En

ceph

alom

yopa

thy

5900

25T

ran

sfer

RN

AM

etab

olic

(mit

och

on-

mt:t

RN

A:E

0013

692

51%

idac

idtr

ansf

erR

NA

wit

hdi

abet

esm

ellit

usdr

ial

tran

slat

ion

):M

R2

loca

len

ergy

defi

cien

cyM

TT

KM

itoc

hon

dria

lly

sin

eM

tM

ER

RF

syn

drom

e;59

0060

Tra

nsf

erR

NA

Met

abol

ic(m

itoc

hon

-m

t:tR

NA

:K00

1369

750

%id

tran

sfer

RN

AM

ER

RF/

ME

LA

Sov

er-

dria

ltr

ansl

atio

n):

MR

lap

syn

drom

e;ot

her

s2

loca

len

ergy

defi

cien

cy

(con

tinue

d)


AP

PE

ND

IX

(Con

tinu

ed)

Mol

ecul

ar-

Gen

eC

hr.

OM

IMfu

nct

ion

GO

Dro

soph

ilaFl

yBas

eB

LA

STP

sym

bola

Gen

en

ame

arm

bC

linic

aldi

sord

erc

no.

cate

gory

dB

iolo

gica

lfu

nct

ion

(s)e

hom

olog

(s)f

no.

gE

-val

ueh

MT

TL

1M

itoc

hon

dria

lle

ucin

eM

tM

EL

AS

syn

drom

e59

0050

Tra

nsf

erR

NA

Met

abol

ic(m

itoc

hon

-m

t:tR

NA

:L:U

UR

0013

699

56%

idtr

ansf

erR

NA

1dr

ial

tran

slat

ion

):M

R2

loca

len

ergy

defi

cien

cyM

TT

S1M

itoc

hon

dria

lse

rin

eM

tM

ER

RF/

ME

LA

Sov

erla

p59

0080

Tra

nsf

erR

NA

Met

abol

ic(m

itoc

hon

-m

t:tR

NA

:S:U

CN

0013

706

47%

idtr

ansf

erR

NA

1sy

ndr

ome

dria

ltr

ansl

atio

n):

MR

2lo

cal

ener

gyde

fici

ency

MT

TV

Mit

och

ondr

ial

valin

eM

tL

eigh

syn

drom

e59

0105

Tra

nsf

erR

NA

Met

abol

ic(m

itoc

hon

-m

t:tR

NA

:V00

1370

848

%id

tran

sfer

RN

Adr

ial

tran

slat

ion

):M

R2

loca

len

ergy

defi

cien

cyM

YO5A

Myo

sin

VA

15q

Ele

jald

esy

ndr

ome

1607

77M

otor

prot

ein

Cyt

oske

leto

n:C

NS

deve

l-di

dum

(&¶

)00

1593

3�

300

(neu

roec

tode

rmal

opm

ent/

fun

ctio

n:

mel

anol

ysos

omal

?neu

rotr

ansm

issi

ondi

seas

e)(p

re/p

osts

ynap

tic)

NA

GL

UN

-ace

tyl-�

-d-

17q

Muc

opol

ysac

char

idos

is25

2920

Hyd

rola

seL

ysos

omal

path

way

EST

S:17

2F5T

0014

417

�14

5gl

ucos

amin

idas

ety

peII

IB(g

lyco

sam

inog

lyca

n):

MR

2lo

cal

toxi

city

NB

S1N

ibri

n8q

Nijm

egen

brea

kage

6026

67Pr

otei

n(D

NA

?)D

NA

repa

ir:

CN

Sde

vel-

nbs

0026

198

�33

syn

drom

ebi

ndi

ng

opm

ent/

fun

ctio

nN

DP

Nor

rin

Xp

Nor

rie

dise

ase

3106

00L

igan

d?S

ign

alin

gpa

thw

ayN

one

——

(?gr

owth

fact

or):

?neu

ron

alsu

rviv

alN

DU

FS1

NA

DH

-ubi

quin

one

oxid

o-2q

Mit

och

ondr

ialc

ompl

exI

1576

55O

xido

redu

ctas

eM

etab

olic

(oxi

dati

veN

D75

0017

566

�30

0re

duct

ase

Fe-S

p.1

defi

cien

cyph

osph

oryl

atio

n):

MR

2lo

cal

ener

gyde

fici

ency

ND

UFS

2N

AD

H-u

biqu

inon

eox

ido-

1qE

nce

phal

omyo

path

y60

2985

Oxi

dore

duct

ase

Met

abol

ic(o

xida

tive

CG

1970

,00

3990

9�

300

redu

ctas

eFe

-Sp.

2ph

osph

oryl

atio

n):

MR

CG

1119

132

loca

len

ergy

defi

cien

cyN

DU

FS4

NA

DH

-ubi

quin

one

oxid

o-5q

Lei

ghsy

ndr

ome

6026

94O

xido

redu

ctas

eM

etab

olic

(oxi

dati

veC

G12

203

0031

021

�36

redu

ctas

eFe

-Sp.

4ph

osph

oryl

atio

n):

MR

2lo

cal

ener

gyde

fici

ency

ND

UFS

7N

AD

H-u

biqu

inon

eox

ido-

19p

Lei

ghsy

ndr

ome

6018

25O

xido

redu

ctas

eM

etab

olic

(oxi

dati

veC

G20

14,

CG

9172

0039

669

�66

redu

ctas

eFe

-Sp.

7ph

osph

oryl

atio

n):

MR

2lo

cal

ener

gyde

fici

ency

(con

tinue

d)


AP

PE

ND

IX

(Con

tinu

ed)

Mol

ecul

ar-

Gen

eC

hr.

OM

IMfu

nct

ion

GO

Dro

soph

ilaFl

yBas

eB

LA

STP

sym

bola

Gen

en

ame

arm

bC

linic

aldi

sord

erc

no.

cate

gory

dB

iolo

gica

lfu

nct

ion

(s)e

hom

olog

(s)f

no.

gE

-val

ueh

ND

UFS

8N

AD

H-u

biqu

inon

e11

qL

eigh

syn

drom

e60

2141

Oxi

dore

duct

ase

Met

abol

ic(o

xida

tive

ND

2300

1756

7�

75ox

idor

educ

tase

phos

phor

ylat

ion

):M

RFe

-Sp.

82

loca

len

ergy

defi

cien

cyN

DU

FV1

NA

DH

-ubi

quin

one

11q

Lei

ghsy

ndr

ome,

1610

15O

xido

redu

ctas

eM

etab

olic

(oxi

dati

veC

G91

40,

oth

ers

0031

771

�30

0ox

idor

educ

tase

Ale

xan

der

phos

phor

ylat

ion

):M

Rfl

avop

rote

in1

syn

drom

e2

loca

len

ergy

defi

cien

cyN

EU1

Neu

ram

inid

ase

6pSi

alid

osis

type

II25

6550

Hyd

rola

seL

ysos

omal

path

way

CG

7447

(*)

0035

539

�19

(gly

colip

id):

MR

2lo

cal

toxi

city

NF1

Neu

rofi

brom

in17

qN

euro

fibr

omat

osis

type

I16

2200

Rec

epto

rSi

gnal

ing

path

way

(sm

all/

Neu

rofib

rom

in1

0015

269

�30

0si

gnal

ing

het

erot

rim

eric

(&¶

)pr

otei

nG

prot

ein

s):

?syn

apti

cpl

asti

city

NP

Nuc

leos

ide

14q

Puri

ne

NP

defi

cien

cy16

4050

Tra

nsf

eras

eM

etab

olic

(pur

ine)

:?M

RC

G16

758

(&)

0035

348

�81

phos

phor

ylas

e2

loca

lto

xici

tyN

PC1

Nie

man

n-P

ick

dise

ase

18q

Nie

man

n-P

ick

dise

ase

6076

23T

ran

spor

ter

Lys

osom

alpa

thw

ay(c

ho-

NPC

1,N

PC1b

0024

320

�30

0ty

peC

1ty

pes

C1,

Dle

ster

ol):

MR

2lo

cal

toxi

city

(neu

ron

,gl

ia)

NPC

2N

iem

ann

-Pic

kdi

seas

e14

qN

iem

ann

-Pic

kdi

seas

e60

1015

Tra

nsp

orte

rL

ysos

omal

path

way

(ch

o-C

G72

91(&

)00

3138

1�

24ty

peC

2ty

peC

2le

ster

ol):

MR

2lo

cal

toxi

city

(neu

ron

,gl

ia)

NSD

1N

ucle

arre

cept

orbi

ndi

ng

5qSo

tos

syn

drom

e60

6681

Tra

nsc

ript

ion

Tra

nsc

ript

ion

regu

la-

Mes

-4(&

¶)

0039

559

�11

3SE

Tdo

mai

npr

otei

n1

(cer

ebra

lgi

gan

tism

)re

gula

tor

tion

:C

NS

deve

lop-

men

t/fu

nct

ion

NT

RK

1N

euro

trop

hic

tyro

sin

e1q

Con

gen

ital

inse

nsi

tivi

ty19

1315

Rec

epto

rSi

gnal

ing

path

way

[Ror

,ot

her

s]00

1040

7�

73(T

RK

A)

kin

ase

rece

ptor

type

1to

pain

wit

han

hyd

rosi

s(R

TK

):C

NS

deve

lop-

men

t/fu

nct

ion

(neu

ron

)O

AT

Orn

ith

ine

keto

acid

10q

Gyr

ate

chor

iore

tin

al25

8870

Tra

nsf

eras

eM

etab

olic

(am

ino

acid

):C

G87

82(&

)00

3689

8�

168

amin

otra

nsf

eras

eat

roph

y?M

R2

loca

len

ergy

defi

cien

cyO

CR

LO

culo

cere

bror

enal

Xq

Low

eoc

uloc

ereb

rore

nal

3090

00Ph

osph

atas

eSi

gnal

ing

path

way

(PI)

EG:8

6E4.

5(&

¶)

0023

508

�10

5sy

ndr

ome

ofL

owe

syn

drom

ean

d/or

prot

ein

sort

-in

g:C

NS

deve

lop-

men

t/fu

nct

ion

(mye

lin)

(con

tinue

d)


AP

PE

ND

IX

(Con

tinu

ed)

Mol

ecul

ar-

Gen

eC

hr.

OM

IMfu

nct

ion

GO

Dro

soph

ilaFl

yBas

eB

LA

STP

sym

bola

Gen

en

ame

arm

bC

linic

aldi

sord

erc

no.

cate

gory

dB

iolo

gica

lfu

nct

ion

(s)e

hom

olog

(s)f

no.

gE

-val

ueh

OPH

N1

Olig

oph

ren

in1

Xq

MR

X60

3001

27R

ecep

tor

sign

al-

Sign

alin

gpa

thw

ay(s

mal

lG

raf

(&¶

)00

3068

5�

82in

gpr

otei

nG

):cy

tosk

elet

on(a

ctin

);C

NS

deve

lop-

men

t/fu

nct

ion

OT

CO

rnit

hin

eX

pH

yper

amm

onem

iadu

e31

1250

Tra

nsf

eras

eM

etab

olic

(ure

acy

cle)

:[r

udim

enta

ry]

0003

189

�17

tran

scar

bam

ylas

eto

OT

Cde

fici

ency

MR

2sy

stem

icto

xici

tyPA

HPh

enyl

alan

ine

12q

Phen

ylke

ton

uria

2616

00O

xido

redu

ctas

eM

etab

olic

(am

ino

acid

):H

enn

a(&

)00

0120

8�

153

hyd

roxy

lase

MR

2sy

stem

icto

xici

ty(n

euro

n,

glia

)PA

K3

p21-

acti

vate

dpr

otei

nX

qM

RX

30,

MR

X47

3001

42K

inas

eSi

gnal

ing

path

way

(sm

all

Pak

(&¶

)00

1400

1�

148

kin

ase

3G

):?c

ytos

kele

ton

(act

in);

CN

Sde

velo

p-m

ent/

fun

ctio

nPA

NK

2Pa

nto

then

ate

kin

ase

220

pH

alle

rvor

den

-Spa

tz60

6157

Kin

ase

Met

abol

ic(v

ario

us):

MR

fum

ble

0011

205

�87

dise

ase

2lo

cal

ener

gyde

fici

ency

PAX

8Pa

ired

box

gen

e8

2qT

hyr

oid

dysg

enes

is16

7415

Tra

nsc

ript

ion

Tra

nsc

ript

ion

regu

la-

shav

en(&

)00

0556

1�

59fa

ctor

tion

:en

docr

ine

deve

l-op

men

t/fu

nct

ion

(th

yroi

d)PC

Pyru

vate

carb

oxyl

ase

11q

Lei

ghn

ecro

tizi

ng

2661

50L

igas

eM

etab

olic

:lo

cal

&B

cDN

A:

0027

580

�30

0en

ceph

alop

ath

ysy

stem

icto

xici

ty;

GH

0634

8(&

)n

euro

tran

smis

sion

(glu

tam

ate)

PCC

APr

opio

nyl

-CoA

13q

Prop

ion

icac

idem

ia23

2000

Lig

ase

Met

abol

ic(a

min

oac

id):

CG

2118

(*&

)00

3987

7�

123

carb

oxyl

ase,

MR

2sy

stem

icto

xici

ty�

-sub

unit

PCC

BPr

opio

nyl

-CoA

3qPr

opio

nic

acid

emia

2320

50L

igas

eM

etab

olic

(am

ino

acid

):C

G32

67(*

&)

0042

083

�61

carb

oxyl

ase,

MR

2sy

stem

icto

xici

ty�

-sub

unit

PDH

A1

Pyru

vate

deh

ydro

gen

ase,

Xp

PDH

A1

defi

cien

cy31

2170

Oxi

dore

duct

ase

Met

abol

ic(g

lyco

lysi

s):

CG

7010

,C

G70

2400

2972

1�

118

E1-

�?C

NS

deve

lopm

ent/

fun

ctio

n;

MR

2lo

cal

ener

gyde

fici

ency

PEPD

Pept

idas

eD

(pro

lidas

e)19

qPE

PDde

fici

ency

1701

00H

ydro

lase

Prot

ein

degr

adat

ion

Dip

eptid

ase

C(&

)00

0045

5�

139

(?ex

trac

ellu

lar

mat

rix)

:M

Rca

use

unkn

own

(con

tinue

d)


AP

PE

ND

IX

(Con

tinu

ed)

Mol

ecul

ar-

Gen

eC

hr.

OM

IMfu

nct

ion

GO

Dro

soph

ilaFl

yBas

eB

LA

STP

sym

bola

Gen

en

ame

arm

bC

linic

aldi

sord

erc

no.

cate

gory

dB

iolo

gica

lfu

nct

ion

(s)e

hom

olog

(s)f

no.

gE

-val

ueh

PEX

1Pe

roxi

n1

(per

oxis

ome

7qZ

ellw

eger

syn

drom

e;60

2136

Nuc

leot

ide

Met

abol

ic(o

xida

tion

):l(

3)70

Da

(&)

0013

563

�85

biog

enes

isfa

ctor

1)in

fan

tile

Ref

sum

bin

din

gC

NS

deve

lopm

ent/

dise

ase;

NA

LD

fun

ctio

n(n

euro

nm

igra

tion

,gl

ia)

PEX

2Pe

roxi

som

alm

embr

ane

8qZ

ellw

eger

syn

drom

e;17

0993

Prot

ein

bin

din

gM

etab

olic

(oxi

dati

on):

CG

7081

0035

876

�31

(PX

MP3

)pr

otei

n3

infa

nti

leR

efsu

mC

NS

deve

lopm

ent/

dise

ase

fun

ctio

n(n

euro

nm

igra

tion

,gl

ia)

PEX

3Pe

roxi

n3

(per

oxis

ome

6qZ

ellw

eger

syn

drom

e60

3164

[Pro

tein

Met

abol

ic(o

xida

tion

):C

G68

5900

3648

4�

51bi

ogen

esis

fact

or3)

bin

din

g]C

NS

deve

lopm

ent/

fun

ctio

n(n

euro

nm

igra

tion

,gl

ia)

PEX

5Pe

roxi

som

ere

cept

or1

12p

Zel

lweg

ersy

ndr

ome;

6004

14R

ecep

tor

Met

abol

ic(o

xida

tion

):EG

:63B

12.5

0023

516

�10

2(P

XR

1)N

AL

DC

NS

deve

lopm

ent/

fun

ctio

n(n

euro

nm

igra

tion

,gl

ia)

PEX

6Pe

roxi

n6

(per

oxis

ome

6pZ

ellw

eger

syn

drom

e60

1498

Nuc

leot

ide

Met

abol

ic(o

xida

tion

):C

G11

919

(&)

0033

564

�82

biog

enes

isfa

ctor

6)bi

ndi

ng

CN

Sde

velo

pmen

t/fu

nct

ion

(neu

ron

mig

rati

on,

glia

)PE

X7

Pero

xin

7(p

erox

isom

e6q

Rh

izom

elic

6017

57R

ecep

tor

Met

abol

ic(o

xida

tion

):C

G64

86(&

)00

3592

2�

71bi

ogen

esis

fact

or7)

chon

drod

yspl

asia

CN

Sde

velo

pmen

t/pu

nct

ata

type

Ifu

nct

ion

(neu

ron

mig

rati

on,

glia

)PE

X10

Pero

xin

10(p

erox

isom

e1p

Zel

lweg

ersy

ndr

ome;

6028

59Pr

otei

nbi

ndi

ng

Met

abol

ic(o

xida

tion

):C

G78

6400

3523

3�

26bi

ogen

esis

fact

or10

)N

AL

DC

NS

deve

lopm

ent/

fun

ctio

n(n

euro

nm

igra

tion

,gl

ia)

PEX

12Pe

roxi

n12

(per

oxis

ome

17p

Zel

lweg

ersy

ndr

ome

6017

58Pr

otei

nbi

ndi

ng

Met

abol

ic(o

xida

tion

):C

G36

3900

3128

2�

23bi

ogen

esis

fact

or12

)C

NS

deve

lopm

ent/

fun

ctio

n(n

euro

nm

igra

tion

,gl

ia)

PEX

13Pe

roxi

n13

(per

oxis

ome

2pZ

ellw

eger

syn

drom

e;60

1789

Prot

ein

bin

din

gM

etab

olic

(oxi

dati

on):

CG

4663

0033

812

�29

biog

enes

isfa

ctor

13)

NA

LD

CN

Sde

velo

pmen

t/fu

nct

ion

(neu

ron

mig

rati

on,

glia

)PE

X16

Pero

xin

16(p

erox

isom

e11

pZ

ellw

eger

syn

drom

e60

3360

[Pro

tein

Met

abol

ic(o

xida

tion

):C

G39

4700

3701

9�

32bi

ogen

esis

fact

or16

)bi

ndi

ng]

CN

Sde

velo

pmen

t/fu

nct

ion

(neu

ron

mig

rati

on,

glia

)

(con

tinue

d)


AP

PE

ND

IX

(Con

tinu

ed)

Mol

ecul

ar-

Gen

eC

hr.

OM

IMfu

nct

ion

GO

Dro

soph

ilaFl

yBas

eB

LA

STP

sym

bola

Gen

en

ame

arm

bC

linic

aldi

sord

erc

no.

cate

gory

dB

iolo

gica

lfu

nct

ion

(s)e

hom

olog

(s)f

no.

gE

-val

ueh

PEX

19Pe

roxi

n19

(per

oxis

ome

1qZ

ellw

eger

syn

drom

e60

0279

[Pro

tein

Met

abol

ic(o

xida

tion

):C

G53

2500

3240

7�

13bi

ogen

esis

fact

or19

)bi

ndi

ng]

CN

Sde

velo

pmen

t/fu

nct

ion

(neu

ron

mig

rati

on,

glia

)PG

K1

Phos

phog

lyce

rate

Xq

Hem

olyt

ican

emia

and

3118

00K

inas

eM

etab

olic

(gly

coly

sis)

:Pg

k,C

G99

6100

0307

5�

164

kin

ase

1M

Rdu

eto

PGK

1?C

NS

deve

lopm

ent/

defi

cien

cyfu

nct

ion

(?sy

nap

tic

plas

tici

ty)

PHF6

Plan

th

omeo

dom

ain

-like

Xq

Bor

jeso

n-F

orss

man

-30

0414

Tra

nsc

ript

ion

?Tra

nsc

ript

ion

:?C

NS

de-

Non

e—

—fi

nge

r6

Leh

man

nsy

ndr

ome

regu

lato

rve

lopm

ent/

fun

ctio

nPL

P1Pr

oteo

lipid

prot

ein

1X

qPe

lizae

us-M

erzb

ach

er30

0401

Stru

ctur

alC

NS

deve

lopm

ent/

fun

c-M

600

3709

2�

16di

seas

em

olec

ule

tion

:ol

igod

endr

ocyt

e(m

yelin

)PM

M2

Phos

phom

ann

omut

ase

216

pC

onge

nit

aldi

sord

erof

6017

85Is

omer

ase

Prot

ein

mod

ifica

tion

CG

1068

800

3630

0�

74gl

ycos

ylat

ion

type

Ia(g

lyco

syla

tion

):C

NS

deve

lopm

ent/

fun

ctio

nPO

MG

NT

1N

-Ace

tylg

luco

sam

inyl

-1p

Mus

cle-

eye-

brai

ndi

seas

e60

6822

Tra

nsf

eras

ePr

otei

nm

odifi

cati

on[M

gat1

]00

3452

1�

29tr

ansf

eras

eI.

2(g

lyco

syla

tion

):C

NS

deve

lopm

ent/

fun

ctio

n(n

euro

nal

mig

rati

on)

POM

T1

Prot

ein

O-m

ann

osyl

-9q

Wal

ker-

War

burg

6074

23T

ran

sfer

ase

Prot

ein

mod

ifica

tion

rota

ted

abdo

men

(&)

0003

292

�15

8tr

ansf

eras

e1

syn

drom

e(g

lyco

syla

tion

):C

NS

deve

lopm

ent/

fun

ctio

n(n

euro

nal

mig

rati

on)

POU

1F1

POU

dom

ain

clas

s1

3pC

ombi

ned

pitu

itar

y17

3110

Tra

nsc

ript

ion

Tra

nsc

ript

ion

:ve

ntra

lve

ins

0003

995

�47

(PIT

1)tr

ansc

ript

ion

fact

or1

hor

mon

ede

fici

ency

fact

oren

docr

ine

dev/

fun

c-la

ckin

g,ti

on(p

itui

tary

)→

CN

Sot

her

s(*

)de

velo

pmen

t/fu

nct

ion

PPG

B�

-Gal

acto

sida

sepr

otec

tive

20q

Gal

acto

sial

idos

is25

6540

Prot

ein

bin

din

gL

ysos

omal

path

way

(gly

-C

G45

72,

oth

ers

(*)

0038

738

�35

prot

ein

(cat

hep

sin

A)

colip

id):

MR

2lo

cal

toxi

city

(neu

ron

)PP

OX

Prot

opor

phyr

inog

en1q

Var

iega

tepo

rph

yria

6009

23O

xido

redu

ctas

eM

etab

olic

(hem

epr

otop

orph

yrin

ogen

ox-

0020

018

�79

oxid

ase

syn

thes

is):

MR

idas

eca

use

unkn

own

PRPS

1Ph

osph

orib

osyl

pyro

phos

-X

qPR

PS1-

rela

ted

gout

3118

50K

inas

eM

etab

olic

(pur

ine,

CG

6767

(&)

0036

030

�16

1ph

ate

syn

thet

ase

1py

rim

idin

esy

nth

esis

):M

Rca

use

unkn

own

(con

tinue

d)


AP

PE

ND

IX

(Con

tinu

ed)

Mol

ecul

ar-

Gen

eC

hr.

OM

IMfu

nct

ion

GO

Dro

soph

ilaFl

yBas

eB

LA

STP

sym

bola

Gen

en

ame

arm

bC

linic

aldi

sord

erc

no.

cate

gory

dB

iolo

gica

lfu

nct

ion

(s)e

hom

olog

(s)f

no.

gE

-val

ueh

PRSS

12Se

rin

epr

otea

se12

4qA

utos

omal

rece

ssiv

e60

6709

Hyd

rola

sePr

otei

nde

grad

atio

n:

Teq

uila

(&¶

)00

2347

9�

71(n

euro

tryp

sin

)n

onsp

ecifi

cM

RC

NS

deve

lopm

ent/

fun

ctio

n(s

ynap

se)

PSA

PPr

osap

osin

10q

Met

ach

rom

atic

1768

01E

nzy

me

Lys

osom

alpa

thw

ay(g

ly-

Sapo

sin-

rela

ted

0000

416

�27

leuk

odys

trop

hy,

regu

lato

rco

lipid

):M

R2

loca

lPS

AP

defi

cien

cyto

xici

ty(g

lia:

mye

lin)

PTC

HH

omol

ogof

Dro

soph

ila9q

Hol

opro

sen

ceph

aly

7;60

1309

Rec

epto

rSi

gnal

ing

path

way

(Hh

):pa

tche

d(&

)00

0389

2�

127

patc

hed

basa

lce

lln

evus

CN

Sde

velo

pmen

t/sy

ndr

ome

fun

ctio

n(?

neu

ron

iden

tity

,pro

lifer

atio

n)

PTC

H2

Hom

olog

2of

Dro

soph

ila1p

Nev

oid

basa

lce

ll60

3673

Rec

epto

rSi

gnal

ing

path

way

(Hh

):pa

tche

d(&

)00

0389

2�

300

patc

hed

carc

inom

asy

ndr

ome

CN

Sde

velo

pmen

t/fu

nct

ion

(?n

euro

nid

enti

ty,p

rolif

erat

ion

)PT

ENPh

osph

atas

ean

dte

nsi

n10

qC

owde

nsy

ndr

ome;

6017

28Ph

osph

atas

eSi

gnal

ing

path

way

(PI)

:Pt

en(&

¶)

0026

379

�72

hom

olog

Ban

nay

an-Z

onan

aC

NS

deve

lopm

ent/

syn

drom

e;ot

her

sfu

nct

ion

(neu

ron

mig

rati

on/

diff

eren

tiat

ion

)PT

PN11

Prot

ein

-tyro

sin

e12

qN

oon

ansy

ndr

ome

1;17

6876

Phos

phat

ase

Sign

alin

gpa

thw

ay(v

ari-

cork

scre

w(&

¶)

0000

382

�11

4(S

HP2

)ph

osph

atas

e,L

EO

PAR

Dsy

ndr

ome

ous)

:?C

NS

deve

lop-

non

rece

ptor

type

11m

ent/

fun

ctio

nPT

S6-

Pyru

voyl

tetr

a-11

qH

yper

phen

ylal

anin

emia

2616

40L

yase

Met

abol

ic(B

H4

syn

the-

purp

le00

0314

1�

40h

ydro

pter

insy

nth

ase

due

toPT

Sde

fici

ency

sis)

:n

euro

tran

smis

-si

on(a

min

es);

sys-

tem

icto

xici

tyPV

RL

1Po

liovi

rus

rece

ptor

-like

111

qC

left

lip/p

alat

e-60

0644

Cel

lad

hes

ion

Cel

l-cel

lad

hes

ion

:C

NS

Non

e—

—(n

ecti

n1)

ecto

derm

aldy

spla

sia

mol

ecul

ede

velo

pmen

t/fu

nc-

syn

drom

e;ot

her

sti

on(s

ynap

toge

nes

is,

?pla

stic

ity)

PYC

S�-1

-Pyr

rolin

e-5-

carb

oxy-

10q

Hyp

eram

mon

emia

1382

50O

xido

redu

ctas

eM

etab

olic

(am

ino

acid

):C

G74

7000

3714

6�

300

late

syn

thet

ase

MR

2sy

stem

icto

xic-

ity;

?neu

rom

odul

atio

nQ

DPR

Qui

noi

ddi

hyd

ropt

eri-

4pA

typi

cal

2616

30O

xido

redu

ctas

eM

etab

olic

(BH

4):

Dih

ydro

pter

idin

e00

3596

4�

70di

ne

redu

ctas

eph

enyl

keto

nur

ian

euro

tran

smis

sion

redu

ctas

e(a

min

es);

syst

emic

toxi

city

RA

I1R

etin

oic

acid

indu

ced

117

pSm

ith

-Mag

enis

6076

42[T

ran

scri

ptio

n?T

ran

scri

ptio

nre

gula

-n

one

——

syn

drom

ere

gula

tor]

tion

;C

NS

deve

lop-

men

t/fu

nct

ion

:?n

eu-

ron

diff

eren

tiat

ion

(con

tinue

d)


AP

PE

ND

IX

(Con

tinu

ed)

Mol

ecul

ar-

Gen

eC

hr.

OM

IMfu

nct

ion

GO

Dro

soph

ilaFl

yBas

eB

LA

STP

sym

bola

Gen

en

ame

arm

bC

linic

aldi

sord

erc

no.

cate

gory

dB

iolo

gica

lfu

nct

ion

(s)e

hom

olog

(s)f

no.

gE

-val

ueh

REL

NR

eelin

7qN

orm

an-R

ober

ts60

0514

Lig

and

Sign

alin

gpa

thw

ay(v

ari-

non

e—

—lis

sen

ceph

aly

ous)

:C

NS

deve

lop-

syn

drom

em

ent

(neu

ron

mig

ra-

tion

,di

ffer

enti

atio

n)

RSK

2R

ibos

omal

S6ki

nas

e2

Xp

Cof

fin

-Low

rysy

ndr

ome;

3000

75K

inas

eSi

gnal

ing

path

way

S6kI

I(&

¶)

0011

285

�30

0(R

PS6K

A3)

MR

X19

(gro

wth

fact

or):

?CN

Sde

velo

pmen

t/fu

nct

ion

SAR

A2

Sar1

-AD

P-ri

bosy

lati

on5q

Ch

ylom

icro

nre

ten

tion

6076

90N

ucle

otid

eT

ran

spor

t(l

ipid

s):

MR

sar1

(*&

)00

3894

7�

80(S

AR

1B)

fact

or2

dise

ase

wit

hbi

ndi

ng

caus

eun

know

nM

arin

esco

-Sjo

gren

syn

drom

eSC

5DL

Ster

olC

5-de

satu

rase

11q

Lat

hos

tero

losi

s60

2286

Oxi

dore

duct

ase

Met

abol

ic(c

hol

este

rol)

:N

one

——

(SC

5D)

(lat

hos

tero

lsi

gnal

ing

path

way

deh

ydro

gen

ase)

(Hh

);?C

NS

deve

lop-

men

t/fu

nct

ion

SCO

2H

omol

ogof

yeas

tSC

O2

22q

Fata

lin

fan

tile

card

io-

6042

72C

hap

eron

eM

etab

olic

(oxi

dati

veC

G88

8500

3165

6�

56en

ceph

alom

yopa

thy

phos

phor

ylat

ion

):M

R2

loca

len

ergy

defi

cien

cySD

HA

Succ

inat

ede

hyd

roge

nas

e5p

Lei

ghsy

ndr

ome

6008

57O

xido

redu

ctas

eM

etab

olic

(oxi

dati

veSc

s-fp,

CG

5718

0017

539

�30

0co

mpl

exsu

bun

itA

phos

phor

ylat

ion

):M

R2

loca

len

ergy

defi

cien

cySG

SH(H

SS)

N-S

ulfo

gluc

osam

ine

17q

Muc

opol

ysac

char

idos

is60

5270

Hyd

rola

seL

ysos

omal

path

way

CG

1429

1(&

)00

3866

0�

139

sulf

ohyd

rola

sety

peII

IA(g

lyco

sam

inog

lyca

n):

MR

2lo

cal

toxi

city

SHH

Son

ich

edge

hog

7qH

olop

rose

nce

phal

y3

6007

25L

igan

dSi

gnal

ing

path

way

(Hh

):he

dgeh

og(&

¶)

0004

644

�83

CN

Sde

velo

pmen

t(n

euro

nan

dgl

iaid

en-

tity

,di

ffer

enti

atio

n)

SIX

3H

omol

og3

ofD

roso

phila

2pH

olop

rose

nce

phal

y2

6037

14T

ran

scri

ptio

nT

ran

scri

ptio

nre

g:C

NS

Opt

ix(&

¶)

0025

360

�87

sine

ocul

isfa

ctor

deve

lopm

ent

(cel

lfa

te,

diff

eren

tiat

ion

;m

orph

ogen

esis

)SL

C4A

4So

lute

carr

ier

4A4

4qR

enal

tubu

lar

acid

osis

II60

3345

Tra

nsp

orte

rT

ran

spor

t(p

Hre

gula

-N

a-d

rive

nan

ion

0031

899

�30

0(N

BC

1)(N

a-H

CO

3ti

on):

?CN

Sde

velo

p-ex

chan

ger

1(&

)co

tran

spor

ter)

men

t/fu

nct

ion

(neu

ron

,gl

ia)

(con

tinue

d)


AP

PE

ND

IX

(Con

tinu

ed)

Mol

ecul

ar-

Gen

eC

hr.

OM

IMfu

nct

ion

GO

Dro

soph

ilaFl

yBas

eB

LA

STP

sym

bola

Gen

en

ame

arm

bC

linic

aldi

sord

erc

no.

cate

gory

dB

iolo

gica

lfu

nct

ion

(s)e

hom

olog

(s)f

no.

gE

-val

ueh

SLC

5A5

Solu

teca

rrie

r5A

519

pG

enet

icde

fect

inth

yroi

d60

1843

Tra

nsp

orte

rT

ran

spor

t(i

odid

e):

en-

CG

2187

,ot

her

s00

1744

8�

84(N

a-I

sym

port

er)

hor

mon

ogen

esis

Ido

crin

efu

nct

ion

(th

y-ro

id):

CN

Sde

velo

p-m

ent/

fun

ctio

nSL

C6A

8So

lute

carr

ier

6A8

Xq

X-li

nke

dcr

eati

ne

3000

36T

ran

spor

ter

Tra

nsp

ort

(cre

atin

e):

CG

1732

,ot

her

s(*

)00

3991

5�

156

(CR

TR

)(c

reat

ine

tran

spor

ter)

defi

cien

cysy

ndr

ome

CN

Sde

velo

pmen

t/fu

nct

ion

;M

R2

loca

len

ergy

defi

cien

cySL

C7A

7So

lute

carr

ier

7A7

(y

L14

qL

ysin

uric

prot

ein

6035

93T

ran

spor

ter

Tra

nsp

ort

(dib

asic

CG

1607

,ot

her

s00

3984

4�

124

amin

oac

idin

tole

ran

ceam

ino

acid

s):

?MR

2tr

ansp

orte

r1)

syst

emic

toxi

city

SLC

12A

1So

lute

carr

ier1

2A1

(Na-

K-

15q

Bar

tter

syn

drom

ety

peI,

6008

39T

ran

spor

ter

Tra

nsp

ort

(ion

s):

MR

CG

4357

,ot

her

s00

3627

9�

300

(NK

CC

2)C

ltr

ansp

orte

r2)

ante

nat

alca

use

unkn

own

;h

yper

calc

iuri

cfo

rm?s

yste

mic

toxi

city

SLC

12A

6So

lute

carr

ier

12A

615

qA

gen

esis

ofco

rpus

6048

78T

ran

spor

ter

Tra

nsp

ort

(ion

s):

CN

SB

EST

:CK

0151

0(&

)00

2569

8�

300

(KC

C3)

(K-C

lco

tran

spor

ter)

callo

sum

(AC

CPN

)de

velo

pmen

t/fu

nc-

tion

(mye

lin,

neu

ron

)SL

C17

A5

Solu

teca

rrie

r17

A5

6qIn

fan

tile

sial

icac

id60

4322

Tra

nsp

orte

rL

ysos

omal

path

way

(var

i-C

G42

88,

oth

ers

0038

799

�94

(sia

lin)

stor

age

diso

rder

;ou

s):M

R2

loca

ltox

ic-

Salla

dise

ase

ity

(neu

ron

,gl

ia)

SLC

25A

15So

lute

carr

ier

25A

1513

qH

HH

syn

drom

e60

3861

Tra

nsp

orte

rT

ran

spor

t(o

rnit

hin

e):

CG

1628

(&)

0030

218

�71

(OR

NT

1)(o

rnit

hin

eM

R2

syst

emic

toxi

city

tran

spor

ter

1)?a

nd

CN

Sde

velo

p-m

ent/

fun

ctio

nSM

PD1

Sph

ingo

mye

lin11

pN

iem

ann

-Pic

kdi

seas

e,25

7200

Hyd

rola

seL

ysos

omal

path

way

(gly

-C

G33

76(&

)00

3499

7�

124

(ASM

)ph

osph

odie

ster

ase

1ty

peA

colip

id):

MR

2lo

cal

toxi

city

(neu

ron

)SM

SSp

erm

ine

syn

thas

eX

pSn

yder

-Rob

inso

n30

0105

Tra

nsf

eras

eM

etab

olic

(pol

yam

ine)

:C

G43

0000

3627

2�

64sy

ndr

ome

?CN

Sde

velo

pmen

t/fu

nct

ion

(neu

ron

exci

tabi

lity)

SOX

3SR

Y-re

late

dH

MG

-box

3X

qM

Rw

ith

grow

th31

3430

Tra

nsc

ript

ion

Tra

nsc

ript

ion

regu

la-

SoxN

euro

(&¶

)00

2912

3�

25h

orm

one

defi

cien

cyfa

ctor

tion

:C

NS

deve

lop-

men

t/fu

nct

ion

(neu

roge

nes

is)

SOX

10SR

Y-re

late

dH

MG

-box

1022

qW

aard

enbu

rg-S

hah

6022

29T

ran

scri

ptio

nT

ran

scri

ptio

nSo

x100

B(&

)00

2428

8�

29sy

ndr

ome,

neu

rolo

gic

fact

orre

gula

tion

:C

NS

vari

ant

deve

lopm

ent

(mye

lin:

olig

oden

droc

yte

diff

eren

tiat

ion

)

(con

tinue

d)


AP

PE

ND

IX

(Con

tinu

ed)

Mol

ecul

ar-

Gen

eC

hr.

OM

IMfu

nct

ion

GO

Dro

soph

ilaFl

yBas

eB

LA

STP

sym

bola

Gen

en

ame

arm

bC

linic

aldi

sord

erc

no.

cate

gory

dB

iolo

gica

lfu

nct

ion

(s)e

hom

olog

(s)f

no.

gE

-val

ueh

SUO

XSu

lfite

oxid

ase

12q

Sulf

ocys

tein

uria

6068

87O

xido

redu

ctas

eM

etab

olic

(am

ino

acid

s):

CG

7280

0030

966

�13

0M

R2

loca

lto

xici

tySU

RF1

Surf

eit

19q

Lei

ghsy

ndr

ome

1856

20[P

rote

inM

etab

olic

(oxi

dati

veSu

rfei

t1

0029

117

�57

bin

din

g]ph

osph

oryl

atio

n):

MR

2lo

cal

ener

gyde

fici

ency

TA

TT

yros

ine

16q

Tyr

osin

emia

type

II27

6600

Tra

nsf

eras

eM

etab

olic

(am

ino

acid

s):

CG

1461

(&)

0030

558

�12

7am

inot

ran

sfer

ase

?MR

2sy

stem

icto

xici

tyT

BC

ET

ubul

in-s

peci

fic

1qH

ypop

arat

hyr

oidi

sm-

6049

34C

hap

eron

eC

ytos

kele

ton

(mic

ro-

CG

7861

(&¶

)00

3305

5�

61ch

aper

one

Ere

tard

atio

n-

tubu

le):

?CN

Sdy

smor

phis

mde

velo

pmen

t/sy

ndr

ome

fun

ctio

nT

C2

Tra

nsc

obal

amin

II22

qT

C2

defi

cien

cy27

5350

Tra

nsp

orte

rT

ran

spor

t(c

ofac

tor)

:N

one

——

CN

Sde

velo

pmen

t/fu

nct

ion

and

?loc

aln

euro

toxi

city

TD

GF1

Ter

atoc

arci

nom

a-de

rive

d3p

Hol

opro

sen

ceph

aly,

1873

95R

ecep

tor

Sign

alin

gpa

thw

ayN

one

——

(CR

IPT

O)

grow

thfa

ctor

1ot

her

fore

brai

n(n

odal

):C

NS

deve

lop-

defe

cts

men

t/fu

nct

ion

TG

Th

yrog

lobu

lin8q

Gen

etic

defe

ctin

thyr

oid

1884

50L

igan

dH

orm

one

syn

thes

is:

en-

[Ace

tylc

holin

e-00

0002

4�

33h

orm

onog

enes

isV

docr

ine

fun

ctio

n(t

hy-

ster

ase,

oth

ers]

roid

):C

NS

deve

lop-

men

t/fu

nct

ion

TG

IFT

G-in

tera

ctin

gfa

ctor

18p

Hol

opro

sen

ceph

aly

460

2630

Tra

nsc

ript

ion

Tra

nsc

ript

ion

regu

la-

vism

ay,

achi

ntya

0033

748

�25

regu

lato

rti

on:

CN

Sde

velo

p-m

ent/

fun

ctio

n(m

orph

ogen

esis

,?p

rolif

erat

ion

)T

HR

BT

hyr

oid

hor

mon

e3p

Th

yroi

dh

orm

one

1901

60R

ecep

tor

Tra

nsc

ript

ion

regu

la-

E75B

,ot

her

s(*

)00

0056

8�

37re

cept

or�

resi

stan

ceti

on:

endo

crin

efu

nc-

tion

(th

yroi

d):

CN

Sde

velo

pmen

t/fu

nct

ion

TIM

M8A

Tra

nsl

ocas

eof

inn

erX

qM

ohr-

Tra

neb

jaer

g30

0356

Tra

nsp

orte

rT

ran

spor

t(m

itoc

hon

-T

im8

0027

359

�15

(DD

P1)

mit

och

ondr

ial

syn

drom

edr

ia):

met

abol

ic;

MR

mem

bran

e8

2lo

cal

ener

gyde

fici

ency

(con

tinue

d)


AP

PE

ND

IX

(Con

tinu

ed)

Mol

ecul

ar-

Gen

eC

hr.

OM

IMfu

nct

ion

GO

Dro

soph

ilaFl

yBas

eB

LA

STP

sym

bola

Gen

en

ame

arm

bC

linic

aldi

sord

erc

no.

cate

gory

dB

iolo

gica

lfu

nct

ion

(s)e

hom

olog

(s)f

no.

gE

-val

ueh

TM

4SF2

Tra

nsm

embr

ane

4X

qM

RX

5830

0096

Sign

alSi

gnal

ing

path

way

Tet

rasp

anin

29Fb

,00

3207

5�

22su

perf

amily

,tr

ansd

ucer

(in

tegr

in):

?act

inot

her

sm

embe

r2

cyto

skel

eton

;?C

NS

deve

lopm

ent/

fun

ctio

nT

PI1

Tri

osep

hos

phat

e12

pN

onsp

her

ocyt

ic19

0450

Isom

eras

eM

etab

olic

(gly

coly

sis)

:T

rios

eph

osph

ate

0003

738

�88

isom

eras

e1

hem

olyt

ican

emia

MR

2lo

cal

ener

gyis

omer

ase

defi

cien

cy?a

nd

loca

lto

xici

tyT

POT

hyr

oid

pero

xida

se2p

Th

yroi

dh

orm

one

or60

6765

Oxi

dore

duct

ase

Hor

mon

esy

nth

esis

:en

-Pe

roxi

dasi

n(*

&)

0011

828

�14

8to

tal

iodi

dedo

crin

efu

nct

ion

(th

y-or

gan

ifica

tion

defe

ctro

id):

CN

Sde

velo

p-m

ent/

fun

ctio

nT

SC1

Ham

arti

n9q

Tub

erou

ssc

lero

sis

160

5284

Prot

ein

bin

din

gC

ytos

kele

ton

:CN

Sde

vel-

Tsc

100

2631

7�

43op

men

t/fu

nct

ion

(neu

ron

/glia

prol

ifer

-at

ion

,di

ffer

enti

atio

n)

TSC

2T

uber

in16

pT

uber

ous

scle

rosi

s2

1910

92R

ecep

tor

sign

al-

Sign

alin

gpa

thw

ay(s

mal

lgi

gas

(&¶

)00

0519

8�

151

ing

prot

ein

G):

CN

Sde

velo

p-m

ent/

fun

ctio

n(n

eu-

ron

/glia

prol

ifer

atio

n,

diff

eren

tiat

ion

)T

SHB

Th

yroi

d-st

imul

atin

g1p

Con

gen

ital

hyp

oth

yroi

d-18

8540

Lig

and

Sign

alin

gpa

thw

ayN

one

——

hor

mon

e,�

-ch

ain

ism

due

toT

SHB

(het

erot

rim

eric

G):

defi

cien

cyen

docr

ine

fun

ctio

n:

CN

Sde

velo

pmen

t/fu

nct

ion

TSH

RT

hyr

oid-

stim

ulat

ing

14q

Con

gen

ital

6033

72R

ecep

tor

Sign

alin

gpa

thw

ayFs

h(&

)00

1665

0�

113

hor

mon

ere

cept

orh

yper

thyr

oidi

sm,

(het

erot

rim

eric

G):

hyp

oth

yroi

dism

endo

crin

efu

nct

ion

:C

NS

deve

lopm

ent/

fun

ctio

nT

TF1

Th

yroi

dtr

ansc

ript

ion

14q

Con

gen

ital

6006

35T

ran

scri

ptio

nT

ran

scri

ptio

nre

gula

-sc

arec

row

(&)

0028

993

�44

(NK

X2A

)fa

ctor

1h

ypot

hyr

oidi

smw

ith

fact

orti

on:

endo

crin

ede

vel-

chor

eoat

het

osis

opm

ent/

fun

ctio

n(t

hyr

oid)

:C

NS

deve

l-op

men

t/fu

nct

ion

(con

tinue

d)


AP

PE

ND

IX

(Con

tinu

ed)

Mol

ecul

ar-

Gen

eC

hr.

OM

IMfu

nct

ion

GO

Dro

soph

ilaFl

yBas

eB

LA

STP

sym

bola

Gen

en

ame

arm

bC

linic

aldi

sord

erc

no.

cate

gory

dB

iolo

gica

lfu

nct

ion

(s)e

hom

olog

(s)f

no.

gE

-val

ueh

TT

F2T

hyr

oid

tran

scri

ptio

n9q

Con

gen

ital

6026

17T

ran

scri

ptio

nT

ran

scri

ptio

nre

gula

-cr

ocod

ile,

oth

ers

(*)

0014

143

�30

(FO

XE1

)fa

ctor

2h

ypot

hyr

oidi

smfa

ctor

tion

:en

docr

ine

deve

lopm

ent/

fun

ctio

n(t

hyr

oid)

:C

NS

deve

lopm

ent/

fun

ctio

nU

BE3

AU

biqu

itin

-pro

tein

ligas

e15

qA

nge

lman

syn

drom

e60

1623

Smal

lpr

otei

nPr

otei

nde

grad

atio

nC

G61

90(&

¶)

0036

148

�17

5E

3Aco

nju

gati

ng

(pro

teas

ome)

:C

NS

deve

lopm

ent/

fun

ctio

n(n

euro

ndi

ffer

enti

atio

n)

XPA

Xer

oder

ma

pigm

ento

sum

9qX

erod

erm

a27

8700

Prot

ein

(DN

A?)

DN

Are

pair

:C

NS

deve

l-X

pac

0004

832

�50

type

Api

gmen

tosu

mty

peA

bin

din

gop

men

t/fu

nct

ion

ZFH

X1B

Zin

c-fi

nge

rh

omeo

box

1B2q

Hir

sch

spru

ng

6058

02T

ran

scri

ptio

nT

ran

scri

ptio

nre

gula

-[K

r-h1,

oth

ers]

0028

420

�17

(SIP

1)di

seas

e-m

enta

lre

gula

tor

tion

:C

NS

deve

lop-

reta

rdat

ion

syn

drom

em

ent/

fun

ctio

n;

?sig

nal

ing

path

way

ZIC

2Z

inc-

fin

ger

prot

ein

of13

qH

olop

rose

nce

phal

y5

6030

73T

ran

scri

ptio

nT

ran

scri

ptio

nod

dpa

ired

(&)

0003

002

�83

cere

bellu

m2

fact

orre

gula

tion

:C

NS

deve

lopm

ent

(cel

lfa

te,

diff

eren

tiat

ion

;m

orph

ogen

esis

)

?,pr

eced

esfu

nct

ion

ssu

gges

ted

but

not

con

clus

ivel

yde

mon

stra

ted.

aA

lter

nat

ive

gen

esy

mbo

lsus

edco

mm

only

inth

elit

erat

ure

are

inpa

ren

thes

es.

Gen

esm

arke

d“•

••”

wer

efo

und

byth

eO

MIM

sear

chfo

r“c

ogn

itiv

eim

pair

men

t”or

“lea

rnin

gdi

sabi

lity.

”bM

tin

dica

tes

age

ne

inth

em

itoc

hon

dria

lge

nom

e.cA

ddit

ion

aldi

sord

ers

may

also

beca

used

bym

utat

ion

ofth

ese

gen

es.

dB

rack

eted

entr

ies

repr

esen

ta

prop

osed

fun

ctio

n,o

nth

eba

sis

ofth

eav

aila

ble

liter

atur

e,fo

rge

nes

that

are

not

liste

din

GO

orh

ave

been

clas

sifi

edby

GO

as“u

nkn

own

mol

ecul

arfu

nct

ion

.”e2

mea

ns

“sec

onda

ryto

.”fT

he

Dro

soph

ilage

nes

wit

hpr

efixe

sC

G,

BG

,E

G,

EST

S,B

EST

,or

BcD

NA

hav

ebe

enid

enti

fied

only

byge

nom

icse

quen

cin

gpr

ojec

ts(s

eeFl

yBas

eat

htt

p://

flyb

ase.

bio.

indi

ana.

edu/

for

deta

ils).

An

aste

risk

(*)

follo

win

ga

gen

en

ame

indi

cate

sa

hom

olog

that

may

bean

orth

olog

,bu

tit

was

not

poss

ible

toas

sign

orth

olog

stat

uson

lyon

the

basi

sof

BL

AST

resu

lts

and

fun

ctio

nal

dom

ain

alig

nm

ents

.G

ene

nam

esin

brac

kets

are

hom

olog

ous

toth

eh

uman

gen

e,bu

tar

en

otlik

ely

tobe

orth

olog

son

the

basi

sof

reve

rse

BL

AST

anal

ysis

.All

oth

erD

roso

phila

gen

eslis

ted

are

orth

olog

s.T

he

ampe

rsan

dsy

mbo

l(&

)af

ter

anor

thol

ogin

dica

tes

that

itw

asse

lect

edfr

omam

ong

two

orm

ore

hom

olog

ous

gen

es.

Th

epa

ragr

aph

sym

bol

(¶)

afte

ran

orth

olog

indi

cate

sth

atit

isa

“pri

me

can

dida

te”

(Tab

le3)

.gT

he

prefi

xFB

gnbe

fore

each

acce

ssio

nn

umbe

ris

requ

ired

toac

cess

the

entr

yin

FlyB

ase.

Iftw

oor

mor

eh

omol

ogs

are

liste

d,on

lyth

eFl

yBas

eac

cess

ion

num

ber

ofth

ege

ne

prod

ucin

gth

eto

p-sc

orin

gB

LA

STP

alig

nm

ent

isgi

ven

.h

On

lyth

eex

pon

ent

ofth

efo

rwar

dB

LA

STP

E-v

alue

issh

own

.If

two

orm

ore

hom

olog

sar

elis

ted,

only

the

expo

nen

tof

the

top-

scor

ing

BL

AST

Pal

ign

men

tis

show

n.F

ortR

NA

gen

es,

the

perc

enta

geid

enti

ty,

base

don

apa

irw

ise

alig

nm

ent

betw

een

the

Dro

soph

ilaan

dh

uman

sequ

ence

s(u

sin

gL

AL

IGN

),is

show

nin

lieu

ofa

BL

AST

scor

e.iT

he

gen

e-se

quen

cin

gso

ftw

are

used

byth

eD

roso

phila

gen

ome

sequ

enci

ng

proj

ect

(rel

ease

s2

and

3)h

asfa

iled

tore

cogn

ize

that

hom

olog

sof

both

MO

CS2

open

read

ing

fram

esar

epr

esen

t.

Molecular and Comparative Genetics of Mental Retardationgenetic MR disorders. Detailed analyses of 1000 Online Mendelian Inheritance in Man (OMIM) database entries and literature searches

Documents