Wolfram syndrome and WFS1 gene

Clin Genet 2011: 79: 103–117Printed in Singapore. All rights reserved

© 2010 John Wiley & Sons A/SCLINICAL GENETICS

doi: 10.1111/j.1399-0004.2010.01522.x

Review

Wolfram syndrome and WFS1 gene

Rigoli L, Lombardo F, Di Bella C. Wolfram syndrome and WFS1 gene.Clin Genet 2011: 79: 103–117. © John Wiley & Sons A/S, 2010

Wolfram syndrome (WS) (MIM 222300) is a rare multisystemneurodegenerative disorder of autosomal recessive inheritance,also known as DIDMOAD (diabetes insipidus, insulin-deficient diabetesmellitus, optic atrophy and deafness). A Wolfram gene (WFS1 ) has beenmapped to chromosome 4p16.1 which encodes an endoplasmic reticulum(ER) membrane-embedded protein. ER localization suggests that WFS1protein has physiological functions in membrane trafficking, secretion,processing and/or regulation of ER calcium omeostasis. Disturbancesor overloading of these functions induce ER stress responses, includingapoptosis. Most WS patients carry mutations in this gene, but some studiesprovided evidence for genetic heterogeneity, and the genotype–phenotyperelationships are not clear. Here we review the data regardingthe mechanisms and the mutations of WFS1 gene that relate to WS.

Conflict of interest

Nothing to declare.

L Rigoli, F Lombardoand C Di Bella

Department of Pediatrics, UniversityHospital, Messina, Italy

Key words: autosomal recessiveinheritance – mutations – WFS1 gene –Wolfram syndrome

Corresponding author:Dr Luciana Rigoli,Dipartimento di Scienze Pediatriche,pad NI, Policlinico Universitario, 98125Messina, Italy.Tel: +39 0902213111;fax: +39 0902213788;e-mail: [email protected]

Received 27 April 2010, revised andaccepted for publication 27 July 2010

Definition

In 1938, Wolfram and Wagener (1–3) describedeight siblings, aged 3–18 years, four of whomhad juvenile diabetes and optic atrophy (OA),thus providing the first report of Wolfram syn-drome (WS) (MIM 222300). Since the originaldescription of Wolfram and Wagener (1), therehave been more than 200 case reports, adding dia-betes insipidus, renal out-flow tract, neurologicaland other endocrine abnormalities to the clinicalfeatures.

Inheritance of WS has been established asautosomal recessive. The minimum ascertainmentcriteria for the diagnosis of WS are the occurrencetogether of childhood onset (<15 years) diabetesmellitus (DM) and OA (4). According to Khanimet al. (5), who refined the criteria, the diagnosticsymptoms for WS are DM, as well as bilateral,progressive OA, occurring before 15 years of age.

WS is also known as DIDMOAD defined bythe association of Diabetes Insipidus, early-onset,insulin-dependent Diabetes Mellitus, progressiveOptic Atrophy and sensorineural Deafness (4, 6).

Symptoms and natural history

WS is a progressive, neurodegenerative disorder.Non-autoimmune and non-HLA-linked DM pres-ents at an average age of 6 years (range 3 weeks to16 years) and is characterized by rare microvascu-lar complications. It seems to develop slower thanin the more common type 1 diabetes (7). Almostall patients require insulin replacement.

OA presents at an average age of 11 years (6weeks to 19 years), with reduced visual acuity andloss of colour vision. OA is progressive, leadingto vision of 6 of 60 or less in the better eye overan average of 8 years. Most patients go blind.

At an average age of 14 years (3 months to40 years), 73–75% of patients present partialcranial diabetes insipidus and respond well tointranasal or oral desmopressin.

Sensorineural deafness develops at an averageage of 16 years (5–39 years).

Other clinical manifestations include renal tractabnormalities (incontinence and neuropathic blad-der) early in the third decade; cerebellar ataxia,peripheral neuropathy, and psychiatric illness (8)

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early in the fourth decade. Presumed carriers havebeen reported as being predisposed to psychiatricillness (9).

Magnetic resonance imaging scans show gen-eralized brain atrophy, especially in the cerebel-lum, medulla and pons; absence of signal from theposterior pituitary; and reduced signal from opticnerve.

Many subjects develop hypogonadism (4,10–12).

Average age of death is 30 (range 25–49) years,thus demonstrating a more severe natural historycompared with type 1 diabetes (13). WS patientsusually die from central respiratory failure as aresult of brainstem atrophy in their third or fourthdecade (4).

The prevalence of WS is estimated at 1 of770,000 in the United Kingdom, with a carrier fre-quency of 1 in 354 (4). This is significantly lowerthan the reported prevalence of 1 of 100,000 and acarrier frequency of 1 in 100 in a North Americanpopulation, based on the 1 in 175 occurrence ofOA in a juvenile-diabetes clinic (14).

Linkage studies

Affected siblings with unaffected parents, oftenconsanguineous, suggested a recessive mode ofinheritance (14, 15). The similarity in phenotypebetween patients with WS and those with cer-tain types of respiratory chain diseases led tothe investigation of mitochondrial DNA (mtDNA)mutations in WS patients. Two examples ofthese mitochondrial diseases are Leber’s Hered-itary Optic Neuropathy (LHON) and Miopathy,

Encephalomiopathy, Lactic Acidosis, and Stroke-Like episodes (MELAS). DM is a complica-tion in MELAS, and OA is the main feature ofLHON. Previous works described rearrangementsin mtDNA in some sporadic and familiar WScases (16–19). Point mutations in mtDNA cancause DM, OA, and deafness (20–24), three ofthe main clinical features of WS. However, themitochondrial tRNALeu (3243) mutation (4) anddeletions in the mitochondrial genome have beenexcluded in >20 WS patients (10, 25–27).

The mutated nuclear gene in WS was identi-fied in 1998 using genetic mapping and candidategene approaches by an American/Japanese collab-oration (28) and by Tim Strom’s group (29). It wasnamed WFS1 by Inoue et al. (28), and Wolframinby Strom (28, 29).

WFS1/wolframin spanning approximately33.4 kb of genomic DNA on chromosome 4p16.1,consists of eight exons. The start point of transla-tion is in the second exon and produces a peptideproduct that is 890-aminoacid long (wolframin)with an apparent molecular mass of 100 kDa.Wolframin is a hydrophobic and tetrameric pro-tein with nine transmembrane segments andlarge hydrophilic regions at both termini (30)(Figs 1 and 2).

A study by El-Shanti et al. (31) identified apotential second locus, designed WFS2 (MIM604928), which mapped to chromosome 4q22-24following linkage analysis of three large, consan-guineous Jordanian families, containing 16 patientswith WS. These patients had features in additionto those previously described in WS. There was

Fig. 1. WFS1 gene which comprises eight exons; exon 1 is non-coding.

Fig. 2. Hypotetical structure of wolframin protein with localization of the transmembrane region.

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absence of diabetes insipidus in all affected fam-ily members. Several patients had profound uppergastrointestinal ulceration and bleeding.

An extensive phenotypic analysis showed addi-tional symptoms in individual with WS2, such assignificant bleeding tendency, as well as a defec-tive platelet aggregation with collagen (32), whichhas not been previously described in families withWS1.

Amr et al. (33) identified a single missensemutation in the CISD2 gene (MIM 611507)in three consanguineous families of Jordaniandescent with WS studied by El-Shanti et al. (31).Like wolframin, the CISD2 -encoded protein, ERIS(endoplasmic reticulum intermembrane small pro-tein), also localizes to the endoplasmic reticulum(ER) (33).

Function of the WFS1 gene

Wolframin is a resident component of the ER (34)with an Ncyt/Clum orientation in the ER mem-brane (30), and in the ER, it seems to be anintegral, endoglycosidase H-sensitive membraneglycoprotein (34). The ER has many roles, whichinclude post-translational modification, folding andassembly of newly synthesized proteins such asinsulin. Perturbations in ER function cause animbalance between these processes, leading toaccumulation of misfolded and unfolded proteinsin the organelle, a state called ER stress. Recently,it has been shown that WFS1 has a crucial role inthe negative regulation of a feedback loop of theER stress signalling network and prevents secre-tory cells, such as pancreatic β-cells, from deathcaused by dysregulation of this signalling path-way (35). Indeed, WFS1 negatively regulates akey transcription factor involved in ER stress sig-nalling, activating transcription factor 6α (ATF6α),through the ubiquitin-proteasome pathway. ATF6αis a type II ER transmembrane transcription fac-tor (36). There are two isoforms of ATF6, ATF6αand ATF6β, with fairly ubiquitous tissue distri-bution. The α-isoform has been shown to besolely responsible for transcriptional induction ofER chaperones (37) Using yeast two-hybrid anal-ysis, Zatyka et al. (38) found that the C-terminaldomain of WFS1, which is positioned in the ERlumen, bound the C-terminal domain (aminoacids652-890) of the ER-localized Na+/K+ ATPasebeta-1 subunit (ATP1B1).

The mature sodium pump is located in theplasma membrane, but it is present transiently inthe ER during maturation. Na/K ATPase deficiencyhas a crucial role in apoptosis and in neuraldegenerative disease. A Na/K ATPase deficiency

in several organs can be induced by mutations inWFS1, leading to the development of WS. Also,hearing loss may be caused by alterations of potas-sium circulation in the inner ear, which is the resultof the disruption of the wolframin–Na/K ATPaseb1 subunit interaction.

Other studies suggested a possible role ofwolframin in protein biosynthesis, modification/folding, trafficking and/or regulation of Ca2+homeostasis and an involvement in the regulationof ER stress (38–43).

Research findings indicated that wolframin mayhelp maintain the correct cellular level of chargedcalcium atoms (calcium ions) by controlling howmuch is stored in the ER (44).

A recent study has demonstrated that wolframinis a calmomodulin (CaM)-binding protein. It hasbeen shown that CaM targets many cellular pro-teins to provide a wide range of Ca2+ signaltransduction (45). With a proteomic approach, ithas been hypothesized that CaM could inter-act with the N-terminal cytoplasmic domain(residue 2-285) and, in particular, that the Ca2+CaM-binding region in wolframin is located fromGlu90 to Trp186. Three mutations (Ala127Thr,Ala134THR, and Arg178Pro) that were foundin WS completely abolish CaM binding ofwolframin (43).

WFS1 gene and main symptoms of WS

Messenger RNA (mRNA) analyses of the WFS1gene have revealed expression in a variety oftissues (28, 29). This protein is expressed in all celltypes (heart, brain, placenta, lung, liver, skeletalmuscle, kidney and pancreas).

Diabetes insipidus

Arginine vasopressin-synthesizing neurons aredistributed in the supraoptic nucleus and the mag-nocellular part of the paraventricular hypothalamicnucleus (46). A detailed histochemical analysisof the distribution of wolframin (Wfs1 ) mRNAin the brain of developing mice has been car-ried out in a recent study. It was found that inthe supraoptic nucleus and the magnocellular partof the paraventricular hypothalamic nucleus ofthe mice, Wfs1 mRNA expression is of a rela-tively constant strength during development, andthis mRNA expression is weak during postnatallife (47). These data suggest that diabetes insipidusin WS patients is caused by neuronal dysfunc-tions of these nuclei resulting from loss-of-functionmutations in the WFS1 gene (48). Moreover, inthe brain of WS patients with diabetes insipidus,

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not only does vasopressin neuron loss occur inthe supraoptic nucleus but also there is a defectin vasopressin precursor processing (48). Thus, inthe mice, the Wfs1 protein has a crucial role inthe survival of neurons and in vasopressin pre-cursor processing from birth to early adult in thesupraoptic nucleus, and the magnocellular part ofthe paraventricular hypothalamic nucleus (47).

Diabetes mellitus

Wolframin is highly expressed in the pancreas (30,40) and it may help fold a protein precursor ofinsulin (called proinsulin) into the mature hormonethat controls blood glucose levels (40).

It has been shown that expression in pancreaticislets is much greater than in pancreatic exocrinecells. Islet β-cells are the major site of WFS1expression. This expression is also found in δ-cells,but not in α-cells. WFS1 expression is transcrip-tionally upregulated by ER stress-inducing chemi-cal insults (40).

Wolframin deficiency in mice leads to progres-sive loss of β-cells, impaired glucose tolerance andcell cycle progression, accompanied by the activa-tion of ER stress/unfolded protein response (UPR)pathways and enhanced susceptibility to apopto-sis (41, 49, 50). UPR coordinates the temporarydownregulation of protein translation, the upregu-lation of ER chaperones, folding machinery, andER-associated degradation in order to reduce theworkload on the ER protein processing and foldingmachinery and prevent the accumulation of mis-folded proteins (51).

Thus, WFS1 seems to play a role in the normalfunction of β-cells, but little is known about itsfunction during embryogenesis.

A close relationship between WFS1 proteinand the mesenchimal and/or epithelial interactionsin pancreatic development has been found (52).Recently, a study has demonstrated that Wfs1protein is localized to the mesenchyme in the ratpancreas by immunofluorescence. Therefore, Wfs1could be involved in many aspects of pancreaticdevelopment (53).

Optic atrophy

Optic nerve atrophy is required for diagnosis ofWS (6).

Some experimental studies on monkey andmouse retina have demonstrated that wolframinis primarily localized in retinal ganglion cells(RGCs), cells in the inner nuclear layer, photore-ceptors, and in glial cells in the proximal portionof the optic nerve (54–56). One question is how

WFS1 mutations contribute to optic nerve atrophyin Wolfram patients. As wolframin is abundant inhuman RGC cell bodies and the initial portions ofthe axons, a WFS1 dysfunction in the ER of thecell body itself could lead to protein deficits inprotein synthesis, deficits in axonal transport, and,ultimately, optic nerve atrophy.

Deafness

The function of wolframin in the inner ear and themechanisms by which missense mutations causehearing loss have not been extensively explored.

The expression of wolframin is widely dis-tributed in different cochlear cell types, includinginner and outer hair cells, a variety of support-ing cells, and cells of the lateral wall, spiral gan-glion, and vestibule (57). It has been localizedin the mouse coclea at different developmentalstages from birth to postnatal day 35 (57). Thus,it is possible that WFS1 contributes to both thedevelopment and maintenance of cells in the audi-tory system including the coclea. Moreover, sen-sorineural deafness in WS patients is induced notonly by dysfunctional inner ear cells but also bydysfunctional neurons in the auditory-related struc-tures of the brain.

In the inner ear, wolframin may help maintainthe proper levels of calcium ions or other chargedparticles that are essential for hearing (57).

The majority of causative deafness mutationshave been identified in exon 8, which contains theconserved C-terminal domain. This domain seemsto have a crucial function in the cochlea (57, 58);the p.Lys836Asn mutation is also located in thisdomain (58).

Neurological and psychiatric symptoms

In WS patients, neurological complications andpsychiatric disorders are common. One study onrats has reported high expression of Wfs1 mRNAand protein in selected areas of the limbic systemincluding the amygdaloid area, hippocampal CA1region, olfactory tubercles and superficial layerof the piriform allocortex (34). Neuroanatomicalstudies suggest that the lack of WFS1 protein func-tion can be related to several neurological andpsychiatric symptoms found in WS (59).

Frequently, WS patients are affected by episodesof severe depression, psychosis, or organic brainsyndrome, as well as impulsive verbal and phys-ical aggression (8). It has been suggested that theWFS1 gene has a role in the neurophysiopathologyof impulsive suicide (59) and hospitalization forpsychiatric diseases in WS patients (60). However,

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these data have not been confirmed by other stud-ies in patients affected by major depression andbipolar disorder (61–66).

Kawano et al. (47) found that in the mice,weak Wfs1 mRNA signals are distributed in theraphe nuclei and nucleus coeruleus from birth toearly adulthood. These nuclei are related to mooddisorders (67).

Thus, in WS patients, loss-of-function mutationsin the WFS1 gene impair the functions of theraphe nuclei and of the nucleus coeruleus, predis-posing the patient to major depression and bipolardisorder.

A recent study demonstrated that Wfs1 -deficientmice displayed increased anxiety in a stressfulenvironment. These symptoms are probably linkedto reduced expression of α1 and α2 subunits ofGABAA receptors in the temporal lobe and frontalcortex (68).

Reproductive biology and endocrinology

It has been found that some WS patients areaffected by anterior pituitary dysfunction. More-over, in male patients, the presence of primarygonadal atrophy and hypergonadotropic hypogo-nadism has been described (4, 6, 10, 69).

In a recent study, Noormets et al. (70) foundthat Wfs1 -deficient (Wfs1 KO) male mice areaffected by reduced fertility. It is known thatWfs1 KO mice are more susceptible to ER stress-induced apoptosis than wild-type mice. Wfs1 isalso expressed in the testis of mice (70), and thusthe increased ER stress in the testes of Wfs1 KOmice may cause changes in sperm morphology andreduced number of spermatogenic cells.

Instead, it is unlikely that impaired fertility inthese mice is caused by altered gonadotrophinlevels (70, 71).

WS and mutations

Genetic analyses in WS have identified a widespectrum of mutations (Table 1; 5, 28, 29, 53,72–112). In many patients, loss-of-function muta-tions such as stop, frameshift (40% of total) andsplice site mutations were found, and missensemutations were detected in approximately 35% ofthe cases (28, 29, 74, 77, 113). The mutationsappeared to be distributed randomly throughout theentire coding sequence of the gene (5). However,in some studies the identified mutations are con-centrated in the largest exon, exon 8 (28, 29, 77,78, 104).

Many of the missense mutations are locatedin the C-terminal hydrophilic part of the pro-tein. Also mutations of the last seven amino acidslead to a full-blown disease phenotype underlin-ing the functional importance of the C-terminus ofwolframin (77, 109).

With the positional cloning approach, Stromet al. (29) characterized wolframin in WS patients.They identified loss-of-function mutations on bothalleles in 5 of 12 WS studied families; compoundheterozygosity was found in nine families. In oneof the families, only a heterozygous stop mutationwas detected. No mutation in either of the twoalleles was found in three families. One of the fam-ilies was reportedly consanguineous. In this study,it has been hypothesized that mutations in exon 1(which was not included in the mutation screen-ing) and intronic mutations including deletions ormutations in the regulatory flanking regions ofthe WFS1 gene could be pathogenic in the stud-ied families. No correlation genotype–phenotypewas found. No mtDNA mutations and/or deletionswere found. In three patients, psychiatric illnesseswere described. Thus, Strom et al. (29) hypothe-sized that haplo-insufficienty of wolframin couldpredispose to psychiatric illness.

By direct DNA sequencing, Hardy et al. (77)screened the entire WFS1 gene in 30 patients from19 British kindred with WS. WFS1 gene mutationswere identified on both alleles in 28 of 30 patientsand on one allele of one patient, confirming agenetic homogeneity in the studied group.

In this study, 24 mutations in the WFS1gene were detected: 8 nonsense mutations, 8missense mutations, 3 in-frame deletions, 1 in-frame insertion, and 4 frameshift mutations. Ofthese, 23 were novel mutations, and most occurredin exon 8. The majority of WS patients werecompound heterozygosites for two mutations.No clear genotype–phenotype relationship wasdetected. There were no obvious mutation hotspotsor clusters. Moreover, Hardy et al. combined theirdata with results of two other studies (28, 29) andunderlined that the majority of frameshifts andnonsense mutations were situated on the predictedtransmembrane domains of the wolframin. In thisstudy, it has also been suggested that molecularscreening of the wolframin mutations in WSpatients requires sequence analysis of exon 8and, possibly, of other exons if no mutations aredetected.

DNA was also screened for deletions, dupli-cations and point mutations of mtDNA, but nopathogenic mutations were found.

Khanim et al. (5) studied 41 WS patients froma UK population. They identified 28 mutations

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Table 1. WFS1 mutations and associated phenotypes

Exon Description Change Consequence Phenotype Reference

Base substitutionsE-4 c.320G>A GGG-GAG G107E Wolfram syndrome Zalloua et al. (72)E-4 c.328T>A TAC>AAC Y110N Wolfram syndrome Giuliano et al. (73)E-4 c.376G>A GCT>ACT A126T Wolfram syndrome Gomez-Zaera

et al. (74)E-4 c.387G>A TGG>TGA W129X Wolfram syndrome Smith et al. (75)E-4 c.397G>A GCC>ACC A133T Wolfram syndrome Khanim et al. (5)E-4 c.397G>A GCC>ACC A133T Wolfram syndrome Giuliano et al. (73)E-4 c.397G>A GCC>ACC A133T Wolfram syndrome Hansen et al. (76)E-4 c.406C>T CAG>TAG Q136X Wolfram syndrome Hardy et al. (77)E-5 c.472G>A GAG>AAG E158K Wolfram syndrome Gasparin et al. (78)E-5 c.482G>A CGG>CAG R161Q LFSHL Tranebjaerg et al. (79)E-5 c.505G>A GAG>AAG E169K Wolfram syndrome Hardy et al. (77)E-5 c.530G>C CGC>CCC R177P Wolfram syndrome Zenteno et al. (80)E-5 c.577A>C AAG>CAG K193Q LFSHL Cryns et al. (81)E-5 c.580C>T CAG>TAG Q194X Wolfram syndrome Hansen et al. (76)E-5 c.631G>A GAT>AAT D211N Wolfram syndrome Sivakumaran et al. (82)E-5 c.631G>A GAT>AAT D211N Wolfram syndrome Van den Ouweland

et al. (83)E-6 c.670C>T CAG>TAG Q224X Wolfram syndrome Khanim et al. (5)E-6 c.676C>T CAG>TAG Q226X Wolfram syndrome Strom et al. (29)E-8 c.817G>T GAG>TAG E273X Wolfram syndrome Hardy et al. (77)E-8 c.873C>A TAC>TAA Y291X Wolfram syndrome Domenech et al. (84)E-8 c.873C>A TAC>TAA Y291X Wolfram syndrome Giuliano et al. (73)E-8 c.874C>T CCC>TCC P292S Wolfram syndrome Hardy et al. (77)E-8 c.887T>G ATC>AGC I296S Wolfram syndrome Hardy et al. (77)E-8 c.906C>A TAC>TAA Y302X Wolfram syndrome Hardy et al. (77)E-8 c.935T>G ATG>AGG M312R Schizophrenia Torres et al. (85)E-8 c.937C>T CAC>TAC H313Y Wolfram syndrome Hansen et al. (76)E-8 c.968A>G CAC>CGC H323R Wolfram syndrome Smith et al. (75)E-8 c.977C>T GCG>GTG A326V Suicide Crawford et al. (86)E-8 c.1037C>T CCG>CTG P346L Wolfram syndrome Cano et al. (87)E-8 c.1145T>C CTG>CCG L382P Wolfram syndrome Gasparin et al. (78)E-8 c.1181A>T GAG>GTG E394V Suicide Crawford et al. (86)E-8 c.1277G>A TGC>TAC C426Y Major Depression Torres et al. (85)E-8 c.1294C>G CTG>GTG L432V Schizophrenia, major

depressionTorres et al. (85)

E-8 c.1321G>A GTG>ATG V441M Bipolar Torres et al. (85)E-8 c.1346C>T ACC>ATC T449I Wolfram syndrome D’Annunzio et al. (88)E-8 c.1371G>T AGG>AGT R457S LFSHL Smith et al. (75)E-8 c.1383C>G ACC>AGC T461S Wolfram syndrome Zalloua et al. (72)E-8 c.1495C>T CTC>TTC L499F Suicide Crawford et al. (86)E-8 c.1554G>A ATG>ATA M518I Schizophrenia Torres et al. (85)E-8 c.1554G>A ATG>ATA M518I LFSHL Smith et al. (75)E-8 c.1584T>C TAC>GAC Y528D Wolfram syndrome Zalloua et al. (72)E-8 c.1597C>T CCC>TCC P533S Suicide Crawford et al. (86)E-8 c.1669C>T CTC>TTC L557F LFSHL Smith et al. (75)E-8 c.1672C>T CGC>TGC R558C Schizophrenia Torres et al. (85)E-8 c.1756G>A GCC>ACC A586T Major depression Torres et al. (85)E-8 c.1805C>T GCG-GTG A602V LFSHL Smith et al. (75)E-8 c.1846G>T GCC>TCC A616S LFSHL Liu et al. (89)E-8 c.1871T>C GTG>GCG V624A LFSHL Smith et al. (75)E-8 c.1901A>C AAG>ACG K634T LFSHL Komatsu et al. (90)E-8 c.1957C>T CGC>TGC R653C Diabetes Awata et al. (91)E-8 c.1964A>G GAG>GGG E655G Suicide Crawford et al. (86)E-8 c.1991T>C CTG>CGG L664R Wolfram syndrome Gasparin et al. (78)E-8 c.1997G>A TGG>TAG W666X Wolfram syndrome Hong et al. (92)E-8 c.2007T>G TAT>TAG Y669X Wolfram syndrome Gasparin et al. (78)E-8 c.2005T>C TAT>CAT Y669H LFSHL Tsai et al. (93)

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Table 1. Continued


E-8 c.2012C>T GCG>GTG A671V Suicide Crawford et al. (86)E-8 c.2021G>A GGG>GAG G674E LFSHL Cryns et al. (81)E-8 c.2021G>T GGG>GTG G674V LFSHL Cryns et al. (81)E-8 c.2033G>T TGG>TTG W678L LFSHL Sivakumaran et al. (82)E-8 c.2053C>T CGC>TGC R685C Suicide Crawford et al. (86)E-8 c.2054G>C CGC>CCC R685P LFSHL Bramhall et al. (94)E-8 c.2068T>G TGC>GGC G690C Wolfram syndrome Zalloua et alet al. (72)E-8 c.2096C>T ACG>ATG T699M LFSHL Bespalova et al. (95)E-8 c.2096C>T ACG>ATG T699M LFSHL Cryns et al. (81)E-8 c.2096C>T ACG>ATG T699M LFSHL Tranebjaerg et al. (79)E-8 c.2105G>A GGC>GAC G702N Wolfram syndrome Gasparin et al. (78)E-8 c.2115G>C AAG>AAC K705N LFSHL Kunz et al. (96)E-8 c.2119G>A GTC>ATC V707I Wolfram syndrome Zalloua et al. (72)E-8 c.2146G>A GCC>ACC A716T LFSHL Bespalova et al. (95)E-8 c.2146G>A GCC>ACC A716T LFSHL Young et al. (97)E-8 c.2146G>A GCC>ACC A716T LFSHL Smith et al. (75)E-8 c.2146G>A GCC>ACC A716T LFSHL Sivakumaran et al. (82)E-8 c.2146G>A GCC>ACC A716T LFSHL Fukuoka et al. (53)E-8 c.2149G>A GAG>AAG E717K Major depression Torres et al. (85)E-8 c.2185G>A GAC>AAC D729N Diabetes Domenech et al. (98)E-8 c.2209G>A GAG>AAG E737K LFSHL Liu et al. (89)E-8 c.2269C>A CTT>ATT L757I Diabetes Domenech et al. (98)E-8 c.2311G>C GAC > CAC D771H LFSHL Gurtler et al. (99)E-8 c.2312A>G GAC>GGC D771G Schizophrenia Torres et al. (85)E-8 c.2314C>T CGC>TGC R772C Schizophrenia Torres et al. (85)E-8 c.2335G>A GTG>ATG V779M LFSHL Bespalova et al. (95)E-8 c.2356G>A GGC>AGC G786S Schizophrenia Torres et al. (85)E-8 c.2419A>C AGC>CGC S807R LFSHL Cryns et al. (81)E-8 c.2452C>T CGC>TGC R818C Schizophrenia, bipolar Torres et al. (85)E-8 c.2486T>C CTG>CCG L829P LFSHL Bespalova et al. (95)E-8 c.2486T>C CTG>CCG L829P LFSHL Smith et al. (75)E-8 c.2486T>C CTG>CCG L829P LFSHL Smith et al. (75)E-8 c.2524C>T CTC>TTC L842F Wolfram syndrome Zalloua et al. (72)E-8 c.2492G>A GGC>GAC G831D LFSHL Cryns et al. (81)E-8 c.2507A>C AAG>ACG K836T LFSHL Fujikawa et al. (100)E-8 c.2508G>C AAG>AAC K836N LFSHL and autosomal

dominant optic neuropathyHogewind et al. (101)

E-8 c.2530G>A GCC>ACC A844T LFSHL Noguchi et al. (102)E-8 c.2576G>C CGG>CCG R859P LFSHL Gurtler et al. (99)E-8 c.2576G>A CGG>CAG R859Q LFSHL Hildebrand et al. (103)E-8 c.2590G>A GAG>AAG E864K LFSHL Fukuoka et al. (53)E-8 c.2590G>A GAG>AAG E864K LFSHL Fukuoka et al. (53)E-8 c.2596G>A GAC>SSAAC D866N LFSHL Liu et al. (89)E-8 c.2596G>A GAC>AAC D866N Schizophrenia Torres et al. (85)

Small deletionsE-5 c.532 537del6 K178 A179del Wolfram syndrome Colosimo et al. (104)E-5 c.599delT L200fs286X Wolfram syndrome Strom et al. (29)E-6 c.639 642delGGCG A214fsX285 Wolfram syndrome Cano et al. (87)E-8 c.862-1357del1254 delexon8 Wolfram syndrome Smith et al. (75)E-8 c.877delC L293fsX303 Wolfram syndrome Cano et al. (87)E-8 c.1046 1048delTCT F350del Wolfram syndrome Gomez-Zaera et al. (74)E-8 c.1060 1062delTTC F354del Wolfram syndrome Hardy et al. (77)E-8 c.1060 1062delTTC F354del Wolfram syndrome Gomez-Zaera et al. (74)E-8 c.1060 1062delTTC F345del Wolfram syndrome Cano et al. (87)E-8 c.1230 1233delCTCT V412fsX440 Wolfram syndrome Tessa et al. (105)E-8 c.1230 1233delCTCT V412fsX440 Wolfram syndrome Colosimo et al. (104)

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Table 1. Continued


E-8 c.1230 1233delCTCT V412fsX440 Wolfram syndrome van den Ouwelandet al. (83)

E-8 c.1230 1233delCTCT V412fsX440 Wolfram syndrome Giuliano et al. (73)E-8 c.1230 1233delCTCT V412fsX440 Wolfram syndrome Domenech et al. (84)E-8 c.1232 1233delCT S411fsX541 Wolfram syndrome Giuliano et al. (73)E-8 c.1234 1237delGTCT V412SfsX29 Wolfram syndrome Gasparin et al. (78)E-8 c.1240 1242delTTC F414del Wolfram syndrome Giuliano et al. (73)E-8 c.1243 1245delGTC V415del Wolfram syndrome Hardy et al. (77)E-8 c.1243 1245delGTC V415del Wolfram syndrome Smith et al. (75)E-8 c.1243 1245delGTC V415del Wolfram syndrome Giuliano et al. (73)E-8 c.1243 1245delGTC V415del Wolfram syndrome Hansen et al. (76)E-8 c.1243 1245delGTC V415del Wolfram syndrome Sivakumaran et al. (82)E-8 c.1470 1472delGAC V434del Wolfram syndrome Hong et al. (92)E-8 c.1355 1370del16 P451fsX515 Wolfram syndrome Zenteno et al. (80)E-8 c.1362 1377del16 Y454X Wolfram syndrome Tessa et al. (105)E-8 c.1362 1377del16 Y454X Wolfram syndrome Colosimo et al. (104)E-8 c.1362 1377del16 Y454 L459del fsX454 Wolfram syndrome Lombardo et al. (106)E-8 c.1380 1388del9 V461 V463del Wolfram syndrome Strom et al. (29)E-8 c.1401 1403delGCT L468del Wolfram syndrome Giuliano et al. (73)E-8 c.1507 1529del13nt V503fsX517 Wolfram syndrome Cano et al. (82)E-8 c.1546 1548delTTC F516del Wolfram syndrome Colosimo et al. (104)E-8 c.1522 1536del15 Y508 L512del Wolfram syndrome van den Ouweland

et al. (83)E-8 c.1522 1523delTA Y508fsX421 Wolfram syndrome Aluclu et al. (107)E-8 c.1522-1523delTA Y508fsX421 Suicide Aluclu et al. (107)E-8 c.1523 1524delAT Y508fsX541 Wolfram syndrome Strom et al. (29)E-8 c.1523 1524delAT Y508fsX541 Wolfram syndrome Colosimo et al. (104)E-8 c.1525 1537del13 Y509fsX517 Wolfram syndrome van den Ouweland

et al. (83)E-8 c.1549delC R517fsX521 Wolfram syndrome Hardy et al. (77)E-8 c.1611 1624del14 del538 542fsX537 Wolfram syndrome Hardy et al. (77)E-8 c.1620 1622delGTG W540del Wolfram syndrome Colosimo et al. (104)E-8 c.1620 1622delGTG W540del Wolfram syndrome Giuliano et al. (73)E-9 c.1661 1687del27 L554 G562del Wolfram syndrome Giuliano et al. (73)E-8 c.1698 1703del6 L567 F568del Wolfram syndrome Giuliano et al. (73)E-8 c.1699 1704delCTCTTT L567 F568del Wolfram syndrome Hardy et al. (77)E-8 c.1775 1776delTG L592fsX604 Wolfram syndrome Giuliano et al. (73)E-8 c.1949 1950delAT Y650fsX710 Wolfram syndrome Domenech et al. (84)E-8 c.2106 2113delTGCTGTTC F646fs708X Wolfram syndrome Zalloua et al. (72)E-8 c.2262 2263delCT C755fsX757 Wolfram syndrome Khanim et al. (5)E-8 c.2300 2302delTCA Idel767 LFSHL Cryns et al. (81)E-8 c.2433delA S812fs861X Wolfram syndrome Hardy et al. (72)E-8 c.2637-2639delATC 8231/del Wolfram syndrome Zalloua et al. (72)E-8 c.2638 2643delGACTTC D880 F881del Wolfram syndrome Eller et al. (108)E-8 c.2643 2646delCTTT F882SsX69 Wolfram syndrome Gasparin et al. (78)E-8 c.2642 2643delTC F883fsX938 Wolfram syndrome Inoue et al. (28)E-8 c.2642 2643delTC F883fsX938 Wolfram syndrome Smith et al. (75)E-8 c.2646 2649delTTTC F993fsX950 Wolfram syndrome Hansen et al. (76)E-8 c.2648 2651delTCTT F883fsX950 Wolfram syndrome Hardy et al. (77)E-8 c.2648 2651delTCTT F883fsX950 Wolfram syndrome Sam et al. (109)E-8 c.2648 2651delTCTT F883fsX950 Wolfram syndrome Giuliano et al. (73)E-8 c.2649delC F883fsX951 Wolfram syndrome Hansen et al. (76)E-8 c.2649delC F884fsX951 Wolfram syndrome Cano et al. (87)E-8 c.2106delTGCTGTTC F646fs708X Wolfram syndrome Zalloua et al. (72)E-8 c.2637delATC I823/del Wolfram syndrome Zalloua et al. (72)Small insertionsE-3 c.409 424dup16 V142fsX251 Wolfram syndrome Gomez-Zaera et al. (74)E-3 c.409 424dup16 V142fsX251 Wolfram syndrome Pennings et al. (110)E-3 c.409 424dup16 V142fsX251 Wolfram syndrome Domenech et al. (84)

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Table 1. Continued


E-3 c.409 424dup16 V142fsX251 Wolfram syndrome Smith et al. (75)E-3 c.409 424dup16 V142fsX251 Wolfram syndrome Giuliano et al. (73)E-4 c.409 424dup16 V142fsX251 Wolfram syndrome Cano et al. (87)E-8 c.876 877dup1 L293PfsX13 Wolfram syndrome Gasparin et al. (78)E-8 c.937-941dupCACTG L315fsX360 Wolfram syndrome Hansen et al. (71)E-8 c.1029insC 344fsX395 Wolfram syndrome Hofmann et al. (30)E-8 c.1032 1033ins9 344 345insAFF Wolfram syndrome Smith et al. (75)E-8 c.1032 1033ins9 344 345insAFF Wolfram syndrome Inukai et al. (111)E-8 c.1038 1039insC L347fsX396 Wolfram syndrome Eller et al. (108)E-8 c.1109 1110insAAGGC A371fsX443 Wolfram syndrome Nakamura et al. (112)E-8 c.1355 1370dup16 A460HfsX88 Wolfram syndrome Gasparin et al. (78)E-8 c.1440 1441insCTGAAGG L481fsX544 Wolfram syndrome Inoue et al. (28)E-8 c.1504 1505ins24 ins8aa Wolfram syndrome Hardy et al. (77)E-8 c.1581 1582insC Y528fsX542 Wolfram syndrome van den Ouweland

et al. (83)E-8 c.1813 1814insA S605fsX711 Wolfram syndrome Cano et al. (87)E-8 c.2164 2165dup24 N721 M722dup8aa Wolfram syndrome Strom et al. (29)E-8 c.2164 2165dup24 N721 M722dup8aa Wolfram syndrome Colosimo et al. (104)E-8 c.2224 2225insT C742fsX758 Wolfram syndrome Giuliano et al (73)E-8 c.2315 2316insT Y773fsX776 Wolfram syndrome Eller et al. (108)E-8 c.2504 2505insC K836fsX939 Wolfram syndrome Colosimo et al. (104)

LFSHL, low-frequency sensorineural hearing loss.

in the WFS1 gene in 37 patients, including fivenovel mutations. Most patients were heterozygousfor two different mutations. They refined WS asa disease characterized by DM as well as pro-gressive, bilateral OA, occurring before 15 yearsof age. According to these diagnostic criteria andby a mutational analysis of the WFS1 gene, theyidentified at least one mutation in 90% of WSpatients and two mutations in 78% of patients inthe UK population. Moreover, in those patientsin whom no mutations were identified, the AAsuggested searching for other mutations in the pro-moter and/or intronic sequences. In this study,most wolframin alterations were private mutationsand were distributed throughout the gene, particu-larly concentrated in exon 8. No obvious hotspotswere found.

Tessa et al. (105) performed a screening formutations in the WFS1 gene in six unrelated Ital-ian patients. Eight distinct variants were identified,including five missense mutations, one frameshiftmutation, a 16-bp deletion, and an intronic muta-tion. Six changes were new. The frameshift andnonsense mutations encompassed the predictedtransmembrane domains of the wolframin accord-ing to other studies previously described (28,29, 77).

In all, 22 WS patients from 16 Spanish familieswere screened for mutations in the WFS1 -codingregion (74) and in mtDNA. WFS1 mutationswere detected in 75% of families. One of these

mutations, an insertion of 16 bp in exon 4, wasdetected in 50% of Spanish pedigrees. In thisstudy, it has been suggested that the higher inci-dence of this mutation in Spanish families couldbe explained by a founder effect. Ten other muta-tions were identified: seven missense changes, twodeletions, and one nonsense mutation. The typesof mutations detected in the Spanish WS patientswere different from those identified in otherpedigrees (29, 77).

Large mtDNA rearrangements and Leber’sHereditary Optic Neuropathy mutations werefound in four WS families. No correlation betweenWFS1 gene mutations and rearrangements ofmtDNA was found.

Colosimo et al. (104) identified a total of 19 dif-ferent mutations of WFS1 gene in 18 of 19 patients(95%). All these mutations, except one, werenovel, preferentially located in WFS1 exon 8,and include deletions, insertions, duplications, andnonsense and missense changes. In particular, a16-bp deletion in WFS1 codon 454 was foundin five different unrelated nuclear families, themost prevalent alteration in the Italian families.Nine neutral changes and polymorphisms werealso detected.

In a review of the mutational spectrum of theWFS1 gene, Cryns et al. (81) pointed out that themajority (55%) of the WS mutations are inactivat-ing. As homozygosity or compound heterozygosisfor missense mutations were rarely detected in WS,

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the AA supposed that the WS carriers of thesemutations show a relatively mild WS phenotype.The phenotype of patients with two missense muta-tions includes OA, DM, and sometimes deafness,but diabetes insipidus and other clinical complica-tions are absent. In contrast, the phenotype of theWS patients with deletions, insertions, nonsensemutations or splice site mutations is more severe.

Van den Ouweland et al. (83) screened 12 WSpatients from nine Dutch families for mutationsin the WFS1 -coding region and in mtDNA. Sevenmutations in WFS1 were detected in six of ninefamilies: two missense mutations, one frameshiftmutation, one splice donor site mutation, and threedeletions. In addition, a splice variant near the5′UTR of WFS1 was identified. The majority ofthese mutations were identified in the predictedtransmembrane domains of the wolframin (four ofseven). Three of these mutations caused a prema-ture translation stop because of frameshift result-ing in a complete absence of the carboxy-tail ofthe wolframin, which is important for the interac-tion of WFS1 with other, yet unknown, proteins.No alterations of mtDNA were found. This studyconfirmed that WS patients with missense muta-tions have a mild phenotype. Moreover, the genetichomogeneity of the Dutch patients with WS hasbeen underlined.

Smith et al. (75) studied 13 WS patients fromnine families. A total of nine novel mutations andthree new silent polymorphisms were identified.A severe phenotype was seen in patients witha large deletion encompassing most of exon 8,and with mutations in exon 4. Two families werecharacterized by a severe phenotype with devel-opment of neurodegenerative changes in the firstdecade. In one family previously described (28),the mother transmitted a large deletion encom-passing the whole of the exon 8 to three affectedsiblings. Two of the siblings died from brainstem atrophy before 21 years of age. A secondAustralian family with a severe phenotype had achild with central sleep apnea that began at 8 yearsof age. He had two mutations resulting in a severetruncated protein. One of these mutations was a16-bp insertion, which is a common Spanish muta-tion (84). The AA purposed that there is a corre-lation genotype–phenotype in WS patients.

WFS1 variants were identified in eight sub-jects from seven Danish families with WS (76).A mutation was identified in 11 of 14 diseasechromosomes (78.6%). Four of the mutations werenovel. Two subjects were homozygous for onemutation, one subject was compound heterozy-gous for two missense mutations, one subject wascompound heterozygous for a duplication and a

frameshift deletion, and in three families only onemutation was found. In this study, the WS patientsfrom different families had considerable pheno-typic variability, but a less intrafamilial variability.However, no clear genotype–phenotype relation-ship was found.

Giuliano et al. (73) studied a total of 19 WSpatients and 36 relatives from 17 French families.WFS1 mutations were identified on both alleles in16 of 19 patients and on 1 allele out of 3 patients.In all, 25 mutations were identified, 12 of whichwere novel. For the first time, a new homozygousmutation in the splice donor site of exon 7 hasbeen found, which resulted in a severe phenotypewith a young boy presenting with DM, OA, dia-betes insipidus and neurological symptoms at theage of 9.

As regard the other mutations, most patientswere compound heterozygotes. No common found-er mutation or mutational hotspots were found inthe WFS1 gene. In the 36 relatives, 26 heterozy-gote carriers were identified. This study demon-strated a lack of WFS1 gene common mutationsin the French population.

By an analysis of genotype–phenotype relation-ship in these WS patients, the AA hypothesizedthat inactivation of both WFS1 alleles may beassociated with early onset of DM.

Cano et al. (87) described 12 WS patients from11 French families. They identified eight noveland seven previously reported mutations in theWFS1 gene. To analyse a genotype–phenotypecorrelation, they combined the 12 WS patients with19 French cases previously reported by Giulianoet al. (73). Twenty-seven WS patients exhibitingtwo identified mutations of the WFS1 genewere thus selected. The patients were subdividedinto two groups based on WFS1 genotyping:genotype 1 (19 patients) was characterized by theabsence of missense mutations, and genotype 2 (8patients) was characterized by the presence of atleast one missense mutation. Both DM and OAoccurred in WS patients. The age of diagnosisof DM and OA was earlier in patients withgenotype 1 than those with genotype 2. Moreover,the average number of main symptoms existingbefore the age of 10 was significantly higher inpatients carrying two inactivating mutations thanin patients with genotype 2. This study confirmedthat homozygosity or compound heterozygosity formissense mutations results in a ‘mild’ phenotype.On the contrary, WS patients carrying inactivatingmutations exhibit a more severe disease.

These observations were confirmed byD’Annunzio et al. (88) who studied six Italian WSchildren from five unrelated families. In these WS

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patients, severely inactivating mutations resultedin a more severe phenotype than mildly inactivat-ing ones. Moreover, they observed that the samemutation gives very different phenotypes.

In a recent study, 27 Brazilian WS patients from19 families were examined (78). In 26 patients, 15different mutations in the WFS1 gene were iden-tified, among which 9 were novel. All mutationswere situated in exon 8, except for one missensemutation that was found in exon 5. This homozy-gous mutation was associated with a mild pheno-type: onset of DM and OA during adulthood withgood metabolic control being achieved with lowdoses of sulfonylurea.

With regard to mutations in exon 8, noclear genotype–phenotype correlation was demon-strated.

Pathophysiological role of wolframin mutants inWS

Hofmann et al. (30) investigated, for the first time,the molecular mechanisms that cause loss-of-function of wolframin in affected individuals. Byprotein analysis of fibroblast cell lines of WSpatients, they found that stop and frameshift muta-tions of WFS1 cause complete absence of the wol-framin protein rather than synthesis of truncatedspecies. Furthermore, it has been demonstrated thatnonsense WFS1 transcripts are unstable in vivoand that they seem to be recognized and degradedby the cell via a common pathway known as non-sense-mediated mRNA decay (114). The degrada-tion of nonsense WFS1 transcripts prevents thesynthesis of truncation translation products andthis is the molecular mechanism underlying theloss-of-function of wolframin in these patients.Transfection experiments with a missense tran-script (missense mutation R629W) revealed anunexpectedly low steady-state level of WFS1 anda markedly reduced half-time of the wolframinR629W. These data suggest that protein instabilityis responsible for the low wolframin levels in thesecells rather than a functional defect of expressedmutant wolframin.

In 2006, Hofmann and Bauer (42) investigatedthe effect of six different missense mutations andtruncating mutations on the expression level, sta-bility, degradation and the intracellular fate ofWFS1. They found that all mutations led to drasti-cally reduced, steady-state levels of WFS1 protein.Mutated proteins appeared to be rapidly subjectedto proteasomal degradation at an early stage of bio-genesis. No wolframin aggregates were found inpatient cells suggesting that WS is not a diseaseof protein aggregation.

Associated diseases

There appears to be an increased frequency of psy-chiatric illness (9), DM (14), and in some cases,hearing loss (115) in first-degree relatives of WSpatients. This has led to the hypothesis that het-erozygosity for WS gene mutations may be asignificant contributory factor for these illnessesin the general population (47, 59, 60, 62, 63,66, 116–126). Heterozygote carriers have beenreported as 26 times more likely to require hos-pitalization for psychiatric illness (9).

Conclusions

From mutational studies in WS patients, a widespectrum of mutations distributed throughout thecoding sequence of the WFS1/wolframin gene hasbeen found, but no obvious hotspots have beenidentified. The majority of the WFS1 mutations areconcentrated in the exon 8 and are located in theC-terminal hydrophilic part of the protein (28, 29,77, 78, 83, 104). No genotype–phenotype correla-tion has been identified. The function of WFS1 isunknown and it is difficult to assess or predict theeffect of these mutations on protein function andhence their biological relevance. Thus, the diag-nosis of WS remains essentially clinical. We needto know the function of WFS1 and its results indiabetes and neurodegeneration. Identification ofinteracting partners is also a key step in allocatinga function to the WFS1 gene product.

It is possible that mutations of the WFS1 geneinitiate disease, and either secondary genetic locior environmental factors contribute to modifydisease progression. The knowledge of WFS1gene and protein functions is important for therecognition of treatable complications in Wolframpatients, and for their parents, for the possibility ofgenetic counselling. Moreover, the identificationsof precise functions of WFS1 gene could enableresearchers to seek novel therapeutic approaches.

References

1. Wolfram DJ, Wagener HP. Diabetes mellitus and simpleoptic atrophy among siblings: report of four cases. Mayo ClinProc 1938: 13: 715–718.

2. Cooper IS, Rynearson EH, Bailey AA et al. The relation ofspinal cord diseases to gynecomastia and testicular atrophy.Proc Staff Meet Mayo Clin 1950: 25 (12): 320–326.

3. Paley RG, Tunbridge RE. Primary optic atrophy in diabetesmellitus. Diabetes 1956: 5 (4): 295–296.

4. Barrett TG, Bundey SE, Macleod AF. Neurodegenerationand diabetes: UK nationwide study of Wolfram (DIDMOAD)syndrome. Lancet 1995: 346 (8988): 1458–1463.

5. Khanim F, Kirk J, Latif F, Barrett TG. WFS1/wolframinmutations, Wolfram syndrome, and associated diseases. HumMutat 2001: 17 (5): 357–367.

113

Rigoli et al.

6. Barrett TG, Bundey SE. Wolfram (DIDMOAD) syndrome.J Med Genet 1997: 34: 838–841.

7. Ganie MA, Bhat D. Current developments in Wolfram syn-drome. J Pediatr Endocrinol Metab 2009: 22 (1): 3–10.

8. Swift RG, Sadler DB, Swift M. Psychiatric findings inWolfram syndrome homozygotes. Lancet 1990: 336 (8716):667–669.

9. Swift RG, Polymeropoulos MH, Torres R et al. Predisposi-tion of Wolfram syndrome heterozygotes to psychiatric ill-ness. Mol Psychiatry 1998: 3 (1): 86–91.

10. Rigoli L Arrigo T, Corigliano G et al. Mitochondrial DNAstudies and clinical findings in Wolfram syndrome: an Italianmulticenter survey. Diab Nutr Metab 1998: 11: 114–120.

11. Soliman AT, Bappal B, Darwish A et al. Growth hormonedeficiency and empty sella in DIDMOAD syndrome: anendocrine study. Arch Dis Child 1995: 73 (3): 251–253.

12. Borgna-Pignatti C, Marradi P, Pinelli L et al. Thiamine-responsive anemia in DIDMOAD syndrome. J Pediatr 1989:114 (3): 405–410.

13. Kinsley BT, Swift M, Dumont RH et al. Morbidity andmortality in the Wolfram syndrome. Diabetes Care 1995: 18(12): 1566–1570.

14. Fraser FC, Gunn T. Diabetes mellitus, diabetes insipidus, andoptic atrophy. An autosomal recessive syndrome? J MedGenet 1977: 14 (3): 190–193.

15. Gunn T, Bortolussi R, Little JM et al. Juvenile diabetesmellitus, optic atrophy, sensory nerve deafness, and diabetesinsipidus – a syndrome. J Pediatr 1976: 89 (4): 565–570.

16. Rotig A, Cormier V, Chatelain P et al. Deletion of mitochon-drial DNA in a case of early-onset diabetes mellitus, opticatrophy, and deafness (Wolfram syndrome, MIM 222300).J Clin Invest 1993: 91 (3): 1095–1098.

17. Barrientos A, Casademont J, Saiz A et al. Autosomal reces-sive Wolfram syndrome associated with an 8.5-kb mtDNAsingle deletion. Am J Hum Genet 1996: 58 (5): 963–970.

18. Barrientos A, Volpini V, Casademont J et al. A nucleardefect in the 4p16 region predisposes to multiple mitochon-drial DNA deletions in families with Wolfram syndrome.J Clin Invest 1996: 97 (7): 1570–1576.

19. Bundey S, Poulton K, Whitwell H et al. Mitochondrial ab-normalities in the DIDMOAD syndrome. J Inherit Metab Dis1992: 15 (3): 315–319.

20. van den Ouweland JM, Lemkes HH, Ruitenbeek W et al.Mutation in mitochondrial tRNA(Leu)(UUR) gene in a largepedigree with maternally transmitted type II diabetes mellitusand deafness. Nat Genet 1992: 1 (5): 368–371.

21. Kobayashi Y, Momoi MY, Tominaga K et al. A point muta-tion in the mitochondrial tRNA(Leu)(UUR) gene in MELAS(mitochondrial myopathy, encephalopathy, lactic acidosis andstroke-like episodes). Biochem Biophys Res Commun 1990:173 (3): 816–822.

22. Wallace DC, Singh G, Lott MT et al. Mitochondrial DNAmutation associated with Leber’s hereditary optic neuropathy.Science 1988: 242 (4884): 1427–1430.

23. Gomez Zaera M, Miro O, Arias L et al. MitochondrialDNA LHON in alcoholic patiens developing amblyopia.Alcoholism 1999: 35 (1–2): 23–33.

24. Prezant TR, Agapian JV, Bohlman MC et al. Mitochondrialribosomal RNA mutation associated with both antibiotic-induced and non-syndromic deafness. Nat Genet 1993: 4 (3):289–294.

25. Seyrantepe V, Topaloglu H, Simsek E et al. MitochondrialDNA studies in Wolfram (DIDMOAD) syndrome. Lancet1996: 347 (9002): 695–696.

26. Jackson MJ, Bindoff LA, Weber K et al. Biochemical andmolecular studies of mitochondrial function in diabetes

insipidus, diabetes mellitus, optic atrophy, and deafness.Diabetes Care 1994: 17 (7): 728–733.

27. Hofmann S, Bezold R, Jaksch M et al. Wolfram (DID-MOAD) syndrome and Leber hereditary optic neuropathy(LHON) are associated with distinct mitochondrial DNA hap-lotypes. Genomics 1997: 39 (1): 8–18.

28. Inoue H, Tanizawa Y, Wasson J et al. A gene encoding atransmembrane protein is mutated in patients with diabetesmellitus and optic atrophy (Wolfram syndrome). Nat Genet1998: 20 (2): 143–148.

29. Strom TM, Hortnagel K, Hofmann S et al. Diabetes insipidus,diabetes mellitus, optic atrophy and deafness (DIDMOAD)caused by mutations in a novel gene (wolframin) coding fora predicted transmembrane protein. Hum Mol Genet 1998: 7(13): 2021–2028.

30. Hofmann S, Philbrook C, Gerbitz KD et al. Wolfram syn-drome: structural and functional analyses of mutant andwild-type wolframin, the WFS1 gene product. Hum MolGenet 2003: 12 (16): 2003–2012.

31. El-Shanti H, Lidral AC, Jarrah N et al. Homozygosity map-ping identifies an additional locus for Wolfram syndrome onchromosome 4q. Am J Hum Genet 2000: 66 (4): 1229–1236.

32. al-Sheyyab M, Jarrah N, Younis E et al. Bleeding tendencyin Wolfram syndrome: a newly identified feature withphenotype genotype correlation. Eur J Pediatr 2001: 160 (4):243–246.

33. Amr S, Heisey C, Zhang M et al. A homozygous mutation ina novel zinc-finger protein, ERIS, is responsible for Wolframsyndrome 2. Am J Hum Genet 2007: 81 (4): 673–683.

34. Takeda K, Inoue H, Tanizawa Y et al. Wfs1 (Wolfram syn-drome 1) gene product: predominant subcellular localiza-tion to endoplasmic reticulum in cultured cells and neuronalexpression in rat brain. Hum Mol Genet 2001: 10 (5):477–484.

35. Fonseca SG, Ishigaki S, Oslowski CM et al. Wolfram syn-drome 1 gene negatively regulates ER stress signaling inrodent and human cells. J Clin Invest 2010: 120 (3):744–755.

36. Yoshida H, Haze K, Yanagi H et al. Identification of thecis-acting endoplasmic reticulum stress response elementresponsible for transcriptional induction of mammalianglucose-regulated proteins. Involvement of basic leucinezipper transcription factors. J Biol Chem 1998: 273 (50):33741–33749.

37. Osman AA, Saito M, Makepeace C et al. Wolframin expres-sion induces novel ion channel activity in endoplasmic retic-ulum membranes and increases intracellular calcium. J BiolChem 2003: 278 (52): 52755–52762.

38. Zatyka M, Ricketts C da Silva Xavier G et al. Sodium-potassium ATPase 1 subunit is a molecular partner ofWolframin, an endoplasmic reticulum protein involved in ERstress. Hum Mol Genet 2008: 17 (2): 190–200.

39. Yamaguchi S, Ishihara H, Tamura A et al. Endoplasmicreticulum stress and N-glycosylation modulate expression ofWFS1 protein. Biochem Biophys Res Commun 2004: 325(1): 250–256.

40. Fonseca SG, Fukuma M, Lipson KL et al. WFS1 is a novelcomponent of the unfolded protein response and maintainshomeostasis of the endoplasmic reticulum in pancreatic beta-cells. J Biol Chem 2005: 280 (47): 39609–39615.

41. Yamada T, Ishihara H, Tamura A et al. WFS1 -deficiencyincreases endoplasmic reticulum stress, impairs cell cycleprogression and triggers the apoptotic pathway specificallyin pancreatic beta-cells. Hum Mol Genet 2006: 15 (10):1600–1609.

114


42. Hofmann S, Bauer MF. Wolfram syndrome-associated muta-tions lead to instability and proteasomal degradation of wol-framin. FEBS Lett 2006: 580 (16): 4000–4004.

43. Yurimoto S, Hatano N, Tsuchiya M et al. Identification andcharacterization of wolframin, the product of the wolframsyndrome gene (WFS1 ), as a novel calmodulin-bindingprotein. Biochemistry 2009: 48 (18): 3946–3955.

44. Takei D, Ishihara H, Yamaguchi S et al. WFS1 proteinmodulates the free Ca(2+) concentration in the endoplasmicreticulum. FEBS Lett 2006: 580 (24): 5635–5640.

45. Xia Z, Storm DR. The role of calmodulin as a signalintegrator for synaptic plasticity. Nat Rev Neurosci 2005: 6(4): 267–276.

46. Armstrong WE. Hypothalamic supraoptic and paraventricularnuclei. In: Paxinos G, ed. The rat nervous system, 3rd edn.San Diego (USA): Elsevier Academic Press, 2004: 369–388.

47. Kawano J, Fujinaga R, Yamamoto-Hanada K et al. Wolframsyndrome 1 (Wfs1 ) mRNA expression in the normal mousebrain during postnatal development. Neurosci Res 2009: 64(2): 213–230.

48. Gabreels BA, Swaab DF, de Kleijn DP et al. The vasopressinprecursor is not processed in the hypothalamus of Wolframsyndrome patients with diabetes insipidus: evidence for theinvolvement of PC2 and 7B2. J Clin Endocrinol Metab 1998:83 (11): 4026–4033.

49. Ishihara H, Takeda S, Tamura A et al. Disruption of the Wfs1gene in mice causes progressive beta-cell loss and impairedstimulus-secretion coupling in insulin secretion. Hum MolGenet 2004: 13 (11): 1159–1170.

50. Riggs AC, Bernal-Mizrachi E, Ohsugi M et al. Mice condi-tionally lacking the Wolfram gene in pancreatic islet betacells exhibit diabetes as a result of enhanced endoplasmicreticulum stress and apoptosis. Diabetologia 2005: 48 (11):2313–2321.

51. Sato BK, Schulz D, Do PH, Hampton RY. Misfolded mem-brane proteins are specifically recognized by the transmem-brane domain of the Hrd1p ubiquitin ligase. Mol Cell 2009:34 (2): 212–222.

52. Gershengorn MC, Hardikar AA, Wei C et al. Epithelial-to-mesenchymal transition generates proliferative human isletprecursor cells. Science 2004: 306 (5705): 2261–2264.

53. Xu R, Xia B, Geng J et al. Expression and localization ofWolfram syndrome 1 gene in the developing rat pancreas.World J Gastroenterol 2009: 15 (43): 5425–5431.

54. Yamamoto H, Hofmann S, Hamasaki DI et al. Wolfram syn-drome 1 (WFS1 ) protein expression in retinal ganglion cellsand optic nerve glia of the cynomolgus monkey. Exp EyeRes 2006: 83 (5): 1303–1306.

55. Kawano J, Tanizawa Y, Shinoda K. Wolfram syndrome 1(Wfs1 ) gene expression in the normal mouse visual system.J Comp Neurol 2008: 510 (1): 1–23.

56. Schmidt-Kastner R, Kreczmanski P, Preising M et al. Ex-pression of the diabetes risk gene wolframin (WFS1 ) in thehuman retina. Exp Eye Res 2009: 89 (4): 568–574.

57. Cryns K, Thys S, Van Laer L et al. The WFS1 gene,responsible for low frequency sensorineural hearing loss andWolfram syndrome, is expressed in a variety of inner earcells. Histochem Cell Biol 2003: 119 (3): 247–256.

58. Fukuoka H, Kanda Y, Ohta S et al. Mutations in the WFS1gene are a frequent cause of autosomal dominant nonsyn-dromic low-frequency hearing loss in Japanese. J Hum Genet2007: 52 (6): 510–515.

59. Sequeira A, Kim C, Seguin M et al. Wolfram syndromeand suicide: evidence for a role of WFS1 in suicidal andimpulsive behavior. Am J Med Genet B NeuropsychiatrGenet 2003: 119B (1): 108–113.

60. Swift M, Swift RG. Wolframin mutations and hospitalizationfor psychiatric illness. Mol Psychiatry 2005: 10 (8): 799–803.

61. Furlong RA, Ho LW, Rubinsztein JS et al. A rare codingvariant within the wolframin gene in bipolar and unipolaraffective disorder cases. Neurosci Lett 1999: 277 (2):123–126.

62. Evans KL, Lawson D, Meitinger T et al. Mutational analysisof the Wolfram syndrome gene in two families withchromosome 4p-linked bipolar affective disorder. Am J MedGenet 2000: 96 (2): 158–160.

63. Middle F, Jones I, McCandless F et al. Bipolar disorder andvariation at a common polymorphism (A1832G) within exon8 of the Wolfram gene. Am J Med Genet 2000: 96 (2):154–157.

64. Ohtsuki T, Ishiguro H, Yoshikawa T et al. WFS1 genemutation search in depressive patients: detection of fivemissense polymorphisms but no association with depressionor bipolar affective disorder. J Affect Disord 2000: 58 (1):11–17.

65. Kato T, Iwamoto K, Washizuka S et al. No association ofmutations and mRNA expression of WFS1/wolframin withbipolar disorder in humans. Neurosci Lett 2003: 338 (1):21–24.

66. Kawamoto T, Horikawa Y, Tanaka T et al. Genetic varia-tions in the WFS1 gene in Japanese with type 2 diabetes andbipolar disorder. Mol Genet Metab 2004: 82 (3): 238–245.

67. Kandel ER. Disorder of mood: depression, mania, andanxiety disorders. In: Kandel ER, Schwartz JH, Jessell TM,eds. Principles of neural science. 4th edn. New York, NY:McGraw-Hill, 2000: 1209–1226.

68. Raud S, Sutt S, Luuk H et al. Relation between increasedanxiety and reduced expression of alpha1 and alpha2 subunitsof GABA(A) receptors in Wfs1 -deficient mice. Neurosci Lett2009: 460 (2): 138–142.

69. Medlej R, Wasson J, Baz P et al. Diabetes mellitus and opticatrophy: a study of Wolfram syndrome in the Lebanese pop-ulation. J Clin Endocrinol Metab 2004: 89 (4): 1656–1661.

70. Noormets K, Koks S, Kavak A et al. Male mice with deletedWolframin (Wfs1 ) gene have reduced fertility. Reprod BiolEndocrinol 2009: 7: 82.

71. Koks S. Luuk H, Plaas M, Vasar E, Expressional profile ofthe WFS1 gene. In: Koks S, Vasar E, eds. WFS1 protein(Wolframin): emerging link between the emotional brain andendocrine pancreas. Kerala, India: Research Signpost, 2008:71–86.

72. Zalloua PA, Azar ST, Delepine M et al. WFS1 mutations arefrequent monogenic causes of juvenile-onset diabetes mellitusin Lebanon. Hum Mol Genet 2008: 17 (24): 4012–4021.

73. Giuliano F, Bannwarth S, Monnot S et al. Wolfram syn-drome in French population: characterization of novel muta-tions and polymorphisms in the WFS1 gene. Hum Mutat2005: 25 (1): 99–100.

74. Gomez-Zaera M, Strom TM, Rodríguez B et al. Presenceof a major WFS1 mutation in Spanish Wolfram syndromepedigrees. Mol Genet Metab 2001: 72 (1): 72–81.

75. Smith CJ, Crock PA, King BR, Meldrum CJ, Scott RJ. Phe-notype-genotype correlations in a series of wolfram syndromefamilies. Diabetes Care 2004: 27 (8): 2003–2009.

76. Hansen L, Eiberg H, Barrett T et al. Mutation analysis of theWFS1 gene in seven Danish Wolfram syndrome families;four new mutations identified. Eur J Hum Genet 2005: 13(12): 1275–1284.

77. Hardy C, Khanim F, Torres R et al. Clinical and moleculargenetic analysis of 19 Wolfram syndrome kindreds demon-strating a wide spectrum of mutations in WFS1. Am J HumGenet 1999: 65 (5): 1279–1290.

115

Rigoli et al.

78. Gasparin MR, Crispim F, Paula SL et al. Identification ofnovel mutations of the WFS1 gene in Brazilian patientswith Wolfram syndrome. Eur J Endocrinol 2009: 160 (2):309–316.

79. Tranebjaerg L, Barrett T, Rendtorff ND. WFS1 -related disor-ders. Pagon RA, Bird TC, Dolan CR, Stephens K, eds. GeneReviews (internet). Seattle (WA): University of Washington,Seattle, 2009: 24.

80. Zenteno JC, Ruiz G, Perez-Cano HJ et al. Familial Wolframsyndrome due to compound heterozygosity for two novelWFS1 mutations. Mol Vis 2008: 14: 1353–1357.

81. Cryns K, Sivakumaran TA, Van den Ouweland JM et al.Mutational spectrum of the WFS1 gene in Wolfram syn-drome, nonsyndromic hearing impairment, diabetes mellitus,and psychiatric disease. Hum Mutat 2003: 22 (4): 275–287.

82. Sivakumaran TA, Lesperance MM. A PCR-RFLP assay forthe A716T mutation in the WFS1 gene, a common cause oflow-frequency sensorineural hearing loss. Genet Test 2002:6 (3): 229–231.

83. Van den Ouweland JM, Cryns K, Pennings RJ et al. Molec-ular characterization of WFS1 in patients with Wolfram syn-drome. J Mol Diagn 2003: 5 (2): 88–95.

84. Domenech E, Gomez-Zaera M, Nunes V. Study of the WFS1gene and mitochondrial DNA in Spanish Wolfram syndromefamilies. Clin Genet 2004: 65 (6): 463–469.

85. Torres R, Leroy E, Hu X et al. Mutation screening ofthe Wolfram syndrome gene in psychiatric patients. MolPsychiatry 2001: 6: 39–43.

86. Crawford J, Zielinski MA, Fisher LJ et al. Is there a relation-ship between Wolfram syndrome carrier status and suicide?.Am J Med Genet 2002: 114: 343–346.

87. Cano A, Rouzier C, Monnot S et al. Identification of novelmutations in WFS1 and genotype-phenotype correlation inWolfram syndrome. Am J Med Genet A 2007: 143A (14):1605–1612.

88. D’Annunzio G, Minuto N, D’Amato E et al. Wolfram syn-drome (diabetes insipidus, diabetes, optic atrophy, and deaf-ness): clinical and genetic study. Diabetes Care 2008: 31 (9):1743–1745.

89. Liu YH, Ke XM, Xiao SF. Heterogenous mutations of Wol-fram syndrome I gene responsible for low frequency nonsyn-dromic hearing loss. Zhonghua Er Bi Yan Hou Tou Jing WaiKe Za Zhi 2005: 10: 764–768.

90. Komatsu K, Nakamura N, Ghadami M et al. Confirmation ofgenetic homogeneity of nonsyndromic low-frequency sen-sorineural hearing loss by linkage analysis and a DFNA6/14mutation in a Japanese family. J Hum Genet 2002: 47:395–399.

91. Awata T, Inoue K, Kurihara S et al. Missense variationsof the gene responsible for Wolfram syndrome (WFS1/wolframin) in Japanese: possible contribution of the Arg456His mutation to type 1 diabetes as a nonautoimmunegenetic basis. Biochem Biophys Res Commun 2000: 268:612–616.

92. Hong J, Zhang YW, Zhang HJ et al. The novel compoundheterozygous mutations, V434del and W666X, in WFS1gene causing the Wolfram syndrome in a Chinese family.Endocrine 2009: 35 (2): 151–157.

93. Tsai HT, Wang YP, Chung SF et al. A novel mutation inthe WFS1 gene identified in a Taiwanese family with low-frequency hearing impairment. BMC Med Genet 2007: 22:8–26.

94. Bramhall NF, Kallman JC, Verrall AM et al. A novel WFS1mutation in a family with dominant low frequency sen-sorineural hearing loss with normal VEMP and EcochG find-ings. BMC Med Genet 2008: 9: 48.

95. Bespalova IN, Van Camp G, Bom SJH et al. Mutations inthe Wolfram syndrome 1 gene (WFS1 ) are a common causeof low frequency sensorineural hearing loss. Hum Mol Genet2001: 10: 2501–2508.

96. Kunz J, Marquez-Klaka B, Uebe S et al. Identification ofa novel mutation in WFS1 in a family affected bylow-frequency hearing impairment. Mutat Res 2003: 525:121–124.

97. Young TL, Ives E, Lynch E et al. Non-syndromic progres-sive hearing loss DFNA38 is caused by heterozygous mis-sense mutation in the Wolfram syndrome gene WFS1. HumMol Genet 2001: 15: 2509–2514.

98. Domenech E, Gomez-Zaera M, Nunes V. WFS1 mutationsin Spanish patients with diabetes mellitus and deafness. EurJ Hum Genet 2002: 10: 421–426.

99. Gurtler N, Kim Y, Mhatre A et al. Two families withnonsyndromic low-frequency hearing loss harbor novelmutations in Wolfram syndrome gene 1. J Mol Med 2005:83 (7): 553–560.

100. Fujikawa T, Noguchi Y, Ito T et al. Additional heterozygous2507A>C mutation of WFS1 in progressive hearing loss atlower frequencies. Laryngoscope 2010: 120 (1): 166–171.

101. Hogewind BF, Pennings RJ, Hol FA et al. Autosomal dom-inant optic neuropathy and sensorineual hearing loss asso-ciated with a novel mutation of WFS1. Mol Vis 2010: 16:26–35.

102. Noguchi Y, Yashima T, Hatanaka A et al. A mutation inWolfram syndrome type 1 gene in a Japanese family withautosomal dominant low-frequency sensorineural hearingloss. Acta Otolaryngol 2005: 11: 1189–1194.

103. Hildebrand MS, Sorensen JL, Jensen M et al. Autoimmunedisease in a DFNA6/14/38 family carrying a novel missensemutation in WFS1. Am J Med Genet A 2008: 146A (17):2258–2265.

104. Colosimo A, Guida V, Rigoli L et al. Molecular detection ofnovel WFS1 mutations in patients with Wolfram syndrome bya DHPLC-based assay. Hum Mutat 2003: 21 (6): 622–629.

105. Tessa A, Carbone I, Matteoli MC et al. Identification ofnovel WFS1 mutations in Italian children with Wolframsyndrome. Hum Mutat 2001: 17 (4): 348–349.

106. Lombardo F, Chiurazzi P, Hortnagel K et al. Clinical picture,evolution and peculiar molecular findings in a very largepedigree with Wolfram syndrome. J Pediatr EndocrinolMetab 2005: 12: 1391–1397.

107. Aluclu MU, Bahceci M, Tuzcu A et al. A new mutationin WFS1 gene (C.1522-1523delTA, Y508fsX421) may beresponsible for early appearance of clinical features ofWolfram syndrome and suicidal behaviour. Neuro EndocrinolLett 2006: 27 (6): 691–694.

108. Eller P, Foger B, Gander R et al. Wolfram syndrome: aclinical and molecular genetic analysis. J Med Genet 2001:38 (11): E37.

109. Sam W, Qin H, Crawford B et al. Homozygosity for a4-bp deletion in a patient with Wolfram syndrome suggestingpossible phenotype and genotype correlation. Clin Genet2001: 59 (2): 136–138.

110. Pennings RJ, Huygen PL, van den Ouweland, JM et al.Sex-related hearing impairment in Wolfram syndrome pa-tients identified by inactivation WFS1 mutations. AudiolNeurootol 2004: 9: 51–62.

111. Inukai K, Awata T, Inoue K et al. Identification of a novelWFS1 mutation (AFF344-345ins) in Japanese patients withWolfram syndrome. Diabetes Res Clin Pract 2005: 69 (2):136–141.

112. Nakamura A, Shimizu C, Nagai S et al. A novel mutation ofWFS1 gene in a Japanese man of Wolfram syndrome with

116


positive diabetes-related antibodies. Diabetes Res Clin Pract2006: 73 (2): 215–217.

113. Bretschger S, Deng L, Caine E et al. Mutational analysis ofthe Wolfram syndrome gene (WFS1 ) in Greek and Dominicanpatients. J Endocrin Genet 2002: 3: 13–19.

114. Frischmeyer PA, Dietz HC. Nonsense-mediated mRNA de-cay in health and disease. Hum Mol Genet 1999: 8 (10):1893–1900.

115. Ohata T, Koizumi A, Kayo T et al. Evidence of an increasedrisk of hearing loss in heterozygous carriers in a Wolframsyndrome family. Hum Genet 1998: 103 (4): 470–474.

116. Ohtsuki T, Ishiguro H, Yoshikawa T et al. WFS1 genemutation search in depressive patients: detection of fivemissense polymorphisms but no association with depressionor bipolar affective disorder. J Affect Disord 2000: 58 (1):11–7.

117. Raud S, Sutt S, Luuk H et al. Relation between increasedanxiety and reduced expression of alpha1 and alpha2 subunitsof GABA(A) receptors in Wfs1 -deficient mice. Neurosci Lett2009: 460 (2): 138–142.

118. Fawcett KA, Wheeler E, Morris AP et al. Detailed investiga-tion of the role of common and low-frequency WFS1 variantsin type 2 diabetes risk. Diabetes 2010: 9 (3): 741–746.

119. Schafer SA, Mussig K, Staiger H et al. A common geneticvariant in WFS1 determines impaired glucagon-like peptide-1-induced insulin secretion. Diabetologia 2009: 52 (6):1075–1082.

120. Hong J, Zhang YW, Zhang HJ et al. The novel compoundheterozygous mutations, V434del and W666X, in WFS1gene causing the Wolfram syndrome in a Chinese family.Endocrine 2009: 35 (2): 151–157.

121. Zalloua PA, Azar ST, Delepine M et al. WFS1 mutationsare frequent monogenic causes of juvenile-onset diabetesmellitus in Lebanon. Hum Mol Genet 2008: 17 (24):4012–4021.

122. Sparsø T, Andersen G, Albrechtsen A et al. Impact ofpolymorphisms in WFS1 on prediabetic phenotypes in apopulation-based sample of middle-aged people with normaland abnormal glucose regulation. Diabetologia 2008: 51 (9):1646–1652.

123. Wasson J, Permutt MA. Candidate gene studies reveal thatthe WFS1 gene joins the expanding list of novel type 2diabetes genes. Diabetologia 2008: 51 (3): 391–393.

124. Plantinga RF, Pennings RJ, Huygen PL et al. Hearing im-pairment in genotyped Wolfram syndrome patients. Ann OtolRhinol Laryngol 2008: 117 (7): 494–500.

125. Hildebrand MS, Sorensen JL, Jensen M et al. Autoimmunedisease in a DFNA6/14/38 family carrying a novel missensemutation in WFS1. Am J Med Genet A 2008: 146A (17):2258–2265.

126. Valero R, Bannwarth S, Roman S et al. Autosomal dominanttransmission of diabetes and congenital hearing impairmentsecondary to a missense mutation in the WFS1 gene. DiabetMed 2008: 25 (6): 657–661.

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