DNA MUTATIONS OF THE CAT The good, the bad and the uglyfelinegenetics.missouri.edu/.../DNA-mutations-of-the-cat...preview.pdf · JFMS CLINICAL PRACTICE 1 C L I N I C A L REVIEW Journal
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
JFMS CLINICAL PRACTICE 1
C L I N I C A L R E V I E W
Journal of Feline Medicine and Surgery (2015) 17, xx–xx
Leslie Lyons
DNA MUTATIONS OF THE CATThe good, the bad and the ugly
Practical relevance: The health of thecat is a complex interaction between itsenvironment (nuture) and its genetics(nature). Over 70 genetic mutations havebeen defined in the cat, many involvediseases, structural abnormalities andclinically relevant health concerns. As more of the cat’s genome is deciphered, less common willbe the use of the term ‘idiopathic’ regarding thediagnosis of diseases and unique health conditions.State-of-the-art health care will include DNAprofiling of the individual cat, and perhaps its tumor,to establish the best modes of treatment. Genetictesting and eventually whole genome sequencingshould become routine diagnostics for felinediseases and health care.Global importance: Cat breeds havedisseminated around the world. Thus, felinepractitioners should be aware of the breedscommon to their region and the mutations found in those regional populations. Specific randombreed populations can also have defined geneticcharacteristics and mutations.Audience: This review is aimed at feline andgeneral practitioners wanting to update and reviewthe basics of genetics, what genetic tests areavailable for cats and the sources for genetictesting. The tables should be useful references in the clinic. Practitioners with a high proportion of cat breeder clientele will highly benefit from thereview.Evidence base: The data present is extractedfrom peer-reviewed publications pertaining to the mutation identification and relevant articlesconcerning the heritable trait and or disease. The author draws upon personal experience and expertise in feline genetics.
Leslie A LyonsPhD
Department of Veterinary Medicine and Surgery, College ofVeterinary Medicine, University of Missouri – Columbia,
The word ‘mutation’ generally conjures negative thoughts and associ-ations, such as Frankenstein’s monster or the X-Men. However, just asFrankenstein’s monster was misunderstood, and the X-Men can usetheir powers for good or evil, so too are the dNA mutations found inthe mammalian genome, including those of the domestic cat. The def-inition of mutation is: ‘a major change; a significant and basic alter-ation’ (Webster’s Third New international dictionary). Consideringheredity, this change implies a difference from the ‘wild type’ – the typ-ical form of an organism as ordinarily encountered in nature. Note,that ‘mutation’ and ‘typical’ does not infer good or bad and ‘ordinarily’applies to the current space and time. indeed, to remove negative con-notations, the current standard is to use the term ‘variant’ instead of‘mutation’ when referring to changes in the dNA.
The wild type cat (Figure 1) is a brown mackerel tabby with moder-ate body and facial conformations. As species evolve, mutation todNA occurs, causing dNA variants and the frequencies of those vari-ants in the population to change due to natural and artificial selection,migrations, popular sires and founder individuals. over time, theextraordinary can become the ordinary. For example, the current ‘ordi-nary’ Persian cat has a highly brachycephalic head type. However, 100years ago, Persians were just long haired cats with a moderately nor-mal face, which would currently be the extraordinary atypical!Although the change in the Persian head structure has been accom-plished by artificial selection, natural selection changes the wild typeover time as well, especially concerning genes and alleles that affect fit-ness (ie, health).
Fitness is reduced any time a cat can not reproduce, has reducedfecundity and/or a shortened reproductive lifespan. Barring commonaccidents and traumas, such as hit-by-car or eaten-by-coyote, the stan-dard housecat, which has access to outdoors, should live generally 12years and succumb to renal disease, hyperthyroidism or lymphosarco-ma. Younger cats with morbidities or mortalities that should generallytake the older and the weaker individuals, likely have alleles that arecompromising their fitness, making them ‘susceptible’ to disease.Many cats live well into their teens, therefore, their genomes likely pos-
sess dNA variants that improve their overallgeneral fitness, improving their ‘resistance’ todisease. Feral cats that live in more naturaland often more harsh environments obtaindNA variants at the same rate as housecatsand pedigreed cats, but often live a shorterlifespan. Besides the cat–cat competitions andtraumas more likely sustained in the openenvironment by a feral cat, dNA variants withpoor fitness will lower the reproductive capa-bilities of a given cat. Therefore, variants thatreduce fitness will more likely be maintainedat a lower frequency in the feral populationthan in our health-managed house and fancybreed cats. Health management allows geneswith poorer fitness to survive and propagatein the species.
overall, most variants are neutral and manyare ‘good’. dNA variants support a species’evolution by conferring advantages to differ-ent selection pressures. A population needsvariation so that given individuals can fendoff viruses and other infections that are thelikely cause of early death in cats, allowing
REV IEW / DNA variants of cats
them to propagate their species that is slightlymore evolved, having better fitness for thecurrent environment. Many ‘good’ dNA vari-ants are just aesthetically pleasing and conferbeauty and uniqueness to individual cats andtheir various breeds. But like any species, catshave some very ‘bad’ and ‘ugly’ dNA vari-ants as well. This article will review ‘the good,the bad and the ugly’ dNA variants of cats,providing the current state of knowledge forgenetic testing and genetic health manage-ment for cats.
The ‘good’ cat variants – variationhumans positively select in cats
To date, over 40 genes with approximately 70dNA variants have been documented to causephenotypic, disease or blood type variationsin the domestic cat.1–3 The clinical descriptionsand phenotypes of each of these diseases andtraits have been curated at the onlineMendelian inheritance in Animals (oMiA)website (http://omia.angis.org.au/home/),which is an invaluable resource comparison ofthe phenotypes across 2216 animal species.4
The 26 genes in Table 1 are often under posi-tive selection in cats, particularly breeds; how-ever, not all of the variants may be considered‘good’ by current standards. once catsbecame domesticated, some of the first notice-able genetic alterations conferred phenotypicvariations, such as fur length, fur type, coatcolors and coat patterns. if you know youralphabet, you can basically remember most ofthe phenotypic genes and loci (see box below)that affect the appearance of a cat (Table 1).Most of these loci were named after traits thatwere first discovered in the domestic mouse,before we knew the genes and the proteinsthey produced.22 A is for Agouti, B is forBrown, C is for Color, D is for Dense, E is forExtension (amber) and so forth. The Color (akaChinchilla) locus was named after a mousephenotype that also presented similarly to the
A gene for a trait is made up of DNA, which makes a protein thatgives rise (directly or indirectly) to the trait of interest. A ‘locus’refers to the place on the chromosome, within the DNAsequence, that the gene is localized. We knew there was a regionin the cat genome that controlled when the yellow and black pig-ment would be turned on and off during the production of a hair.The locus is known as agouti. A given DNA sequence for a geneis called an allele. The normal allele for agouti was defined as ‘A+’and the mutant was defined as ‘a’. Lower case letters implyrecessive alleles, upper case implies dominant alleles. Thus, toget a non-agouti (solid) cat, they have to have two copies of themutant allele, ‘aa’. Once we learned what protein was produced
by the given gene at a specific locus, the gene name is thenredefined after a function of the protein. Agouti is defined by thegene termed, agouti-signaling protein, which is abbreviated toASIP. In cats, ASIP has two alleles, A+ and a. Alleles, loci andgene names are written in italics but the actual protein is writtenin normal font. The wild type allele is designated by a superscript‘+’, which can be an allele with any inheritance pattern.Additional alleles at a gene can be indicated by other superscriptletters that help define the effect. For Agouti, the APbe allele indi-cates that this is the agouti allele from the leopard cat(Prionailurus bengalensis [Pbe]) that is segregating in the Bengalcat breed.
Ge n e s , l o c i a n d a l l e l e s
Figure 1 Single DNA variant effects on coloration in cats. (a) The brown mackerel tabbyconstitutes the wild-type cat. The brown fur is an optical illusion, being banded with black(melanin) and yellow pigment (pheomelanin). Wild-type alleles of genes are marked with asuperscript ‘+’ or are often omitted. Wild-type alleles can be dominant or recessive. Alleles atthe different color loci can be represented for the brown mackerel tabby as: A+-, B+-, C+-, D+-,E+-, i+i+, L+-, o+o+, s+s+, Tm-, titi, w+w+. (b) One variant in Agouti, the non-agouti allele, a, canmake the fur appear solid, although all the other alleles are the same. Only the pheomelanin isreplaced with black pigment in the solid black cat. The solid black cat still has tabby markings.The black cat can be represented as: aa, B+-, C+-, D+-, E+-, i+i+, L+-, o+o+, s+s+, Tm-, titi, w+w+. (c) The silver Oriental shorthair kitten displays the effect of Inhibitor gene that removespheomelanin from the coat and the effect of the Ticked allele that epistatically suppressesTabby markings. A+-, B+-, C+-, D+-, E+-, I-, L+-, o+o+, s+s+,Tia-, w+w+
a
b
c
JFMS CLINICAL PRACTICE 3
REV IEW / DNA variants of cats
Disease/trait (alleles) OMIA Entry
MOI* Phenotype Gene Gene name Mutation
Agouti (A+, a)5000201-9685
AR Banded fur to solid ASIP Agouti-signaling protein c.122_123delCA
Brown (B+, b, bl)6,7001249-9685
AR Brown, light brown color variants TYRP1 Tyrosinase relatedprotein
b = -5IVS6, bl = c.298C>T
Color (C+, Cb, Cs, c)7–9000202-9685
AR Burmese, Siamese color pattern, full albino TYR Tyrosinase cb = c.715G>T, cs = c.940G>A, c = c.975delC
Dilution (D+, d)10000206-9685
AR Black to grey/blue, orange to cream MLPH Melanophilin c.83delT
Dwarfism000299-9685
AD Shortening of long bones unknown unknown unknown
Extension (E+, e) – Amber11001199-9685
AR Brown/red color variant MC1R Melanocortin receptor 1 c.250G>A
Fold (Fd, fd+)000319-9685
AD Ventral ear fold Unpub Unpub Unpub
Gloves (G+, g)12001580-9685
AR White feet KIT KIT c.1035_1036delinsCA
Hairless (Hr+, hr) AR Atrichia KRT71 Keratin 71 c.816+1G>A
Inhibitor (I, i+)001583-9685
AD Absence of phaeomelanin unknown unknown unknown
Japanese Bobtail (J, j+) AD Kinked tail unknown unknown unknown
Kurl (K, k+)000244-9685
AD Rostral curled pinnea unknown unknown unknown
LaPerm000245-9685
AD Curly hair coat unknown unknown unknown
Longhair (L+, l)13,14000439-9685
AR Long fur FGF5 Fibroblast growth factor 5
c.356_367insT, c.406C>T, c.474delT, c.475A>C
Manx (M, m+)15000975-9685
AD Absence/short tail TBOX T – box c.998delT, c.1169delC, and c.1199delC,c.998_1014dup17delGCC
Orange (O, o+) X linked Change in pigment hue unknown unknown unknown
Peterbald001201-9685
AD Hairless, brush coat unknown unknown unknown
Polydactyla (Pd, pd+)16000810-9685
AD Extra toes SHH Sonic hedgehog c.479A>G, c.257G>C, c.481A>T
Rexing (R+, r)17001684-9685
AR Curly hair coat LPAR6 Lysophosphatidic acidreceptor 6
c.250_253delTTTG
Rexing (Re+, re)18001581-9685
AR Curly hair coat KRT71 Keratin 71 c.1108-4_1184del,c.1184_1185insAGTTGGAG,c.1196insT
Rexing (RS, rs+)19001712-9685
AD Curly hair coat KRT71 Keratin 71 c.445-1G>C
Spotting (S, s+)20000214-9685
Co-D Bicolor/van white KIT KIT 7125ins FERV1 element
Tabby(TM, tb)21001429-9685
AR Blotched/classic pattern TAQPEP Transmembraneaminopeptidase Q
S59X, T139N, D228N, W841X
Ticked (Ta, t)001484-9685
AD No Tabby pattern unknown unknown unknown
White (W, w+)20000209-9685
AD Loss of pigmentation KIT KIT FERV1 LTR ins
Wide-band AR? Length of pheomelanin band in hair unknown unknown unknown
*Mode of inheritance of the non-wild type variant. A ‘+’ implies the wild type allele when known. In reference to the mutant allele, AD implies autosomal dominant, AR implies autosomal recessive, co-D implies co-dominant. OMIA: Online Mendelian Inheritance in Animals (http://omia.angis.org.au/home/) entries provides links to citations and clinical descriptions of the phenotypes and the diseases. Presented citations are for the causative variant discovery
Table 1 The phenotypic traits of the domestic cat
D th n
4 JFMS CLINICAL PRACTICE
REV IEW / DNA variants of cats
coloration of the Siamese cat, having colorpresenting only on its cooler extremities. TheDense (Dilute) locus affects the amount andplacement of pigment in the hair shaft, givingthe illusion that a cat is grey or blue. Alsoknown as dilution, blue cats only have blackpigment, but the refractive qualities of the hairshaft cause the illusion of a lighter pig-ment.23,24 The coat color variants are commonto all cats and are appropriate for genetic typ-ing in all breeds and populations.
Together with L for Longhair (fur), S forSpotting, T for Tabby, O for Orange, W forWhite, these loci (A – D, I, L, S, T, O and W)control the major phenotypic traits of cats thatoccurred before the development of catbreeds. Many early geneticists studied thecoat colors of cats to understand basic inheri-tance patterns. Orange is a yet unknown geneon the X chromosome in cats.25,26 BecauseOrange is sex-linked, its inheritance pattern isvery different between males and females,males being more likely to be orange sincethey have only one X chromosome. Orangewas one of the first loci to be geneticallymapped to a specific chromosome, for anyspecies!27–30 Longhair has four different vari-ants that have likely occurred in differentregions of the world and are more or lessprevalent in certain breeds (Figure 2).13,14 Agene for tabby patterns has long been known,but it was recently shown that another gene
controls the expression of the Tabby locus andhence the tabby phenotype (Figure 3).21,31 TheTabby locus (TAQPEP) controls theblotched/classic tabby pattern (tb). However,a second gene locus, dubbed Ticked is nowconsidered to turn tabby patterns on and off.The historically known ticked tabby pheno-type (tabby Abyssinian, Ta) is at this secondlocus, which is not yet identified. The actualpattern is then controlled by TAQPEP (Tabby)and other modifier genes as well.
Spotting and White are two very interestingand complex loci. The gene was recently iden-tified, demonstrating that full white and bicol-or white are alleles at the oncogene calledKIT.20 KIT is also responsible for the gloving ofthe white feet in Birmans, thus having at leastthree alleles.12 However, white spotting isvery complex in most domesticated species;for a good example, examine horse spottinggenes and their alleles.32,33 Thus, KIT may notexplain all white spotting in cats and the asso-ciation with deafness has not beenelucidated.34–36 White spotting is also associat-ed with the domestication of foxes and is like-ly associated with our other domesticatedspecies.37 You can see the first signs of domes-tication of the wild type cat in Figure 1, noticethe white spot on the neck. in cats, the Spottinglocus, now known to be KIT, has at least twoalleles, wild type and spotting.38 one copyappears to make a bicolor cat (Figure 2), whiletwo copies appear to produce a high white,‘Van’ patterned cat. However, other allelesmay be present as white spotting patterns inthe Ragdoll breed are difficult to predict, eventhough they seem similar to those found inother breeds. For example, the white ‘mittens’of some Ragdolls is not controlled by the samedNA variants at the white ‘gloves’ in theBirman.12 The control of white spots on theneck and belly is also unknown, althoughmany of these presentations could be to ran-dom midline closure defects of melanocyte
Figure 2 Longhair of domestic cat breeds. A variety of cats have long fur, but differentcausal variants in the gene fibroblast growth factor 5 (FGF5) exist. Ragdolls (a) have a variant that likely derived in the USA, Persians (b) have the ancient variant that derivedfrom the Near East and is common to most longhaired breeds, Norwegian Forest cats (c)have a variant common to Nordic race cats and Maine Coons (d) may have a fourth variantlikely also derived in the USA. The Maine Coon and Norwegian Forest cat are also bicolor atthe Spotting locus, Ss
Figure 3 Tabby patterns of cats are complex. The Abyssinian (a) displays a variant at likelythe Ticked locus (Tia) that turns off all patterning of the Tabby locus (tabby aby or tickedtabby), no matter what allele present at Tabby. The American Shorthair (b) has the allele atthe Ticked locus (ti) that allows the display of the two recessive blotched (tb) alleles at theTabby locus to produce a classic or blotched tabby. The Ocicat (c) has the allele at theTicked locus (ti) that allows the display of the alleles at the Tabby locus, which are likelymodified by other genes to form the spots. The modifier genes are not clearly resolved
a
b
c
a b
c d
JFMS CLINICAL PRACTICE 5
REV IEW / DNA variants of cats
migration.Thus, many of the ‘good’ dNA variants of
cats confer their aesthetical qualities andmany more recent dNA variants have beenidentified once cat breeding established.Newer variants, such as many of the fur types,are unique and breed defining variants. Someof the earliest phenotypes noted for a breedwere the Cornish Rex39 and devon Rex pre-sentations.40 These curly coated cats becamesome of the first novelty breeds.41,42 Morerecently, hairless cats (Sphynx),43 Selkirk Rex44
and Peterbalds45 have breed defining fur typevariants that are scientifically documented.other rare breeds, such as LaPerm(http://www.tica.org/cat-breeds/item/228)and Tennesse Rex (http://www.ten-nesseerex.com/) have not been defined buthave recognized curly coated cat variants .
A few of the dNA variants listed in Table 1may not be considered ‘good’ by current catbreeding standards. indeed, many of the coatcolor variants, such as White and Spotting maybe detrimental in the feral state, especiallysince they have not been documented in wild-cats (Felis silvestris). The Manx dNA alter-ations are lethal in utero in the homozygousstate and many Manx cats have issues withlameness, incontinence and constipation.46–49
The discovery of the Tailless variants has alsorevealed that Japanese Bobtail50 cats do nothave dNA changes in the same gene and thatthe PixieBob breed has Manx and JapaneseBobtail genetic contributions.15 Many arguethat the hairless phenotypes are ‘too unnatu-ral’ for a cat and they can suffer from potentialhypothermia and sunburn. dwarfism isanother controversial phenotype, propagatedas the Munchkin cat breed. However, thedwarfism breed and the dNA variant havenot been scientifically documented and healthconcerns not yet identified. other well-knownhealth concerns are the Scottish Fold pheno-type, which is associated with osteochon-drodysplasia.51 Many breeders seem to thinkthat osteochrondrodysplasia occurs only inthe homozygous cat. Likely, some disease inheterozygote cats manifestations sub-clinical-ly. in addition, dominant White is associatedwith deafness and increased risks ofmelanomas due to depigmentation and UV-exposure.34–36 deciphering the gene allelesassociated with Scottish Folds and dominantWhite cats will likely help us to understandthe basic biology of the genes and the role ofgenetic modifiers that influence the undesiredand linked health concerns.
Knowledge and understanding of the modeof inheritance and the effect of the aesthetic,phenotypic alleles can support cat health in anindirect manner, by population management.if breeders can be counselled on breeding
schemes that will produce more of the colorand fur type varieties that are preferred andless that are undesired, fewer unwanted catsare produced. Fewer unwanted cats reducecat overpopulation and the likelihood thatindividual cats representing breeds will be rel-egated to animal shelters. in addition, if abreeder has more desired cats and fewerexcess cats, more time, energy and preciousfunds can be designated to the health care ofthe desired cats. importantly, the reduction ofcattery size inherently reduces stress andstress-associated health issues, such as upperrespiratory diseases, urinary tract diseasesand feline infectious peritonitis. Thus, the cor-rect genetic management of a simple coatcolor trait may indirectly improve the healthof the entire cattery.
The ‘bad’ cat variants – variationhumans negatively select in cats
Although current genetics focuses on dNAalterations that affect specific genes, some ofthe earliest genetic testing for any species wasthe examination of the full set of chromo-somes (karyotype) of an individual to deter-mine whether the normal number andarrangement of chromosomes were present(Figure 4). Sex chromosome aneuploidies
Figure 4 Chromosomes of the domestic cat. Giemsa banding(G-banding) of the cat chromosomes helps to define catchromosomes by the placement and thickness of the light and dark bands on the chromosomes. Cat chromosomes can also be easily distinguished by size and shape. Cats havethree large metacentric chromosomes (A1 to A3), four largesubtelomeric chromosomes (B1 to B4), two medium-sizemetacentrics (C1 to C2), four small subtelomerics (D1 to D4),three small metacentrics (E1 to E3) and two small acrocentrics(F1 and F2). The X chromosome is midsize and subtelomeric,similar to chromosome B4. Two X chromosomes implies thecat is a female. Karyotype courtesy of Lutz Froenicke, PhD
Knowledge andunderstandingof the mode ofinheritance andthe effect ofthe aesthetic,phenotypicalleles cansupport cathealth in anindirect
manner, bypopulationmanagement.
6 JFMS CLINICAL PRACTICE
REV IEW / DNA variants of cats
(losses) and trisomies of small acrocentric(chromosomes with no short [p] – arm) chro-mosomes are typically associated withdecreased fertility and syndromes that dis-play distinct morphological abnormalities.Turner’s Syndrome (Xo), Klinefelter’sSyndrome (XXY)52,53 and chimerisms havebeen documented in the domestic cat. Becausethe cat has a highly recognizable X-linkedtrait,27–30 Orange, tortoiseshell and calico (tor-toiseshell and white) male cats were the firstfeline suspects of sex chromosomal abnormal-ities. Karyotypic studies of male tortoiseshellcats have shown that they are often mosaics,or chimeras, being XX/XY in all or some tis-sues.28,53–60
Although gene-based assays are commonmethods to determine if a cat with ambiguousgenitalia61 or a poor reproductive history hasa chromosomal abnormality, karyotypes arestill often performed. Veterinarians can stillrequest karyotypic studies on cats from specif-ic commercial laboratories. domestic catshave an easily distinguishable karyotype con-sisting of 18 autosomal chromosomes and theXY sex chromosome pair, resulting in a 2N
complement of 38 chromosomes for the catgenome62 (Figure 2). Cat chromosomes areclearly defined by size; centromere position;distinctive giemsa banding patterns of theshort (p) and long (q) arms of each chromo-some; and the presence of only a few smallacrocentric chromosomes. Although a sequen-tial numbering of the chromosomes has beensuggested,63 the historical classification ofchromosomes into morphologic groups hasbeen retained for the cat (Figure 4). Group Abeing large metacentrics, group B large sub-telomeric chromosomes, group C as medium-size metacentrics, group d as small subtelom-erics, group E as small metacentrics andgroup F as small acrocentrics. The X chromo-some is midsize and subtelomeric, similar tochromosome B4. As in most mammals, the Ychromosome is small and has few genes, butdoes possess regions that can pair with the Xchromosome, forming pseudoautosomalregions (REF).
The alignment of genes on chromosomes incats is very similar to the genomic organiza-tion in humans.64 Humans have their genesdistributed onto 22 autosomes, therefore only
Disease/trait (alleles) OMIA Entry
MOI* Phenotype Gene Gene name Mutation
AB Blood Type (A+, b)70000119-9685
AR Determines Type B CMAH cytidine monophospho-N-acetylneuraminic acid hydroxylase
c.1del-53_70, c.139G>A
Craniofacial defect AR Craniofacial defect unpub unpub unpub
Gangliosidosis 171000402-9685
AR Lipid storage disorder(GM1)
GLB1 Galactosidase, beta 1 c.1457G>C
Gangliosidosis 27201462-0985
AR Lipid storage disorder(GM2)
HEXB Hexominidase B c.1356del-1_8,c.1356_1362delGTTCTCA
Gangliosidosis 26801462-0985
AR Lipid storage disorder(GM2)
HEXB Hexominidase B c.39delC
Glycogen Storage Dis. IV73000420-9685
AR Glycogen storagedisorder (GSD)
GBE1 Glycogen branching enzyme 1 IVS11+1552_IVS12-1339del6.2kb ins334 bp
Hypertrophic Cardiomyopathy74000515-9685
AD Cardiac disease (HCM) MYBPC Myosin binding protein C c.93G>C
Hypertrophic Cardiomyopathy75000515-9685
AD Cardiac Disease (HCM) MYBPC Myosin binding protein C c.2460C>T
Hypokalemia76001759-9685
AR Potassium deficiency(HK)
WNK4 WNK lysine deficient protein kinase 4
c.2899C>T
Progressive Retinal Atropy77001244-9685
AR Late onset blindness(rdAC)
CEP290 Centrosomal protein 290kDa IVS50 + 9T>G
Progressive Retinal Atropy78000881-9685
AD Early onset blindness(rdy)
CRX Cone-rod homeobox c.546delC
Polycystic Kidney Disease79000807-9685
AD Kidney cysts (PKD) PKD1 Polycystin 1 c.10063C>A
*Mode of inheritance of the non-wild type variant. Not all transcripts for a given gene may have been discovered or well documented in the cat,mutations presented as interpreted from original publication. A ‘+’ implies the wild type allele when known. In reference to the mutant allele, ADimplies autosomal dominant, AR implies autosomal recessive, co-D implies co-dominant. OMIA: Online Mendelian Inheritance in Animals(http://omia.angis.org.au/home/) entries provides links to citations and clinical descriptions of the phenotypes and the diseases. Presented citationsare for the causative variant discovery
Table 2 Inherited diseases of domestic cats for which a commercial DNA test is available
JFMS CLINICAL PRACTICE 7
REV IEW / DNA variants of cats
a small number of changes are required torearrange the same genes onto 18 autosomes,as found in cats. However, although the catgenome is conserved to humans, certain well-known chromosomal abnormalities are notfound (Figure 4). For example, an analog todown’s syndrome is not present in the catsince the genes found on human chromosome21 are represented on the mid-sized metacen-teric chromosome C2, which also has genesfrom human chromosome 3. A Trisomy C2would disrupt more genes than a Trisomy 21in humans, thus, more likely early fetal lossthat is never detected.65 The minor chromoso-mal differences that are cytogeneticallydetectable between a domestic cat and anAsian leopard cat are likely the cause of fertil-ity problems in the Bengal cat breed,62 which
is a hybrid between these two species.66 othersignificant chromosomal abnormalities caus-ing common ‘syndromes’ are not well docu-mented in the cat. Several research and commercial laboratories can perform cat chromosomal analyses when provided a liv-ing tissue, such as a skin biopsy for fibroblastculturing or whole blood for the analysis ofwhite blood cells.
The first gene specific dNA variants identi-fied in cats were for gangliosidosis and mus-cular dystrophy, discovered in 199467,68 asthese diseases had well defined phenotypesand known genes (candidate genes) withdNA alterations in humans. Most diseases areidentified in pedigreed cat breeds, which are asmall percentage of the cat population of theworld, perhaps at most 10–15% in the USA.69
Laboratory and webpage Region University research affiliate IDCat test*Disease Color Blood Coat
*Tests reference to those listed in Tables 1 and 2. If a laboratory offers only one or two tests, those tests are listed, otherwise the number of tests theyoffer for cats is presented. PKD and the HCMs are the most popular cat tests offerings. †PennGen also offers tests for diseases in Table 5 that arenot of concern to the cat breeds or cat population in general
Table 3 Domestic cat DNA testing laboratories
8 JFMS CLINICAL PRACTICE
REV IEW / DNA variants of cats
The genetically characterized diseases andhealth concerns for specific cat breeds are pre-sented in Table 2. Most of the identified dis-ease tests in cats that are very specific tobreeds and populations are available as com-mercial genetic tests offered by university-associated and private laboratories (Table 3).These dNA variants should be monitored bycat breed registries and become the cat dNAalterations that are most familiar to veterinarypractitioners as they are useful diagnostics.Polycystic kidney disease (PKd) is the mostprevalent genetic disease in cats and animportant diagnostic for early kidney disease(Figure 5). The prevalence of PKd in Persianswas estimated at 30–38% worldwide, prior tothe introduction of the genetic test.82–84
Because of cross breeding with Persians,many other breeds, such as British Shorthairs,American Shorthairs, Selkirk Rex and ScottishFolds (Figure 6), also need to be screened forPKd.85–87 The discovery of the hypokalemiadNA variant for Burmese cats reveals that agene influencing overall potassium levels incats can also influence blood pressure inhumans.50,88 By considering the breed relation-ships in Table 4, genetic health concerns across
cat populations and breeds can be inferreddue to inheritance (identity by descent) viaoutcrossing.
Some dNA variants that were found in aspecific breed, such as mucopolysaccharidosisType Vi in the Siamese, were found in a spe-cific individual and the variant is not of signif-icant concern in the breed.89,90 Table 5 lists catdNA alterations identified in random bredcats and disease conferring variants that havenot propagated within a breed. These geneticvariants should not be part of routine screen-ing by cat breeders and registries, but clini-cians should know that genetic tests are avail-able for diagnostic purposes, especially fromresearch groups with specialized expertise. ifsimilar conditions are suspected in cats,researchers will generally consider testing forthe known variant as a non-commercial serv-ice and may continue analysis of the entiregene to determine if new dNA alterations canbe identified and causative for this particularcondition. other biomarkers are also availableat these specialized laboratories to help deci-pher between specific conditions, such as thelysosomal storage diseases and metabolismorders.
Figure 5 Polycystic kidney disease in the Persian cat. (a) Severe PKD, (b) mild PKD. Cats can succumb to kidney disease when severe disease is present.Most cats have mild disease and will likely not succumb to renal failure. (c) Ultrasound image of a cat with moderate to severe PKD. Any cat breedsoutcrossing to Persians should also be concerned with PKD. Images courtesy of Steven DiBartola, DVM, PhD and David Biller, DVM
a b c
Figure 6 Persian cat breed family. (a) Scottish Fold, (b) Persian and (c) Selkirk Rex. The Scottish Fold and the Selkirk Rex are derived from random bred catsthat had novel ear and hair coat variants, respectively, and have been molded by crossing with Persians to obtain structure and facial and head morphology.The Selkirk and Scottish Fold are at risk for polycystic kidney disease due to the outcrossing with the Persian. These cats segregate for longhair variantscommon to the Persian and have a variety of coloration variants. The Scottish Fold is an Orange and white tabby (A-, B-, C-, D-, E-, I-, Ll, O-, Ss), the Persianis cream and high white (aa, B-, C-, dd, E-, I-, ll, O-, SS), and the Selkirk is a black smoke (aa, B-, C-, D-, E-, I-, ll, oo, ss)
a b c
JFMS CLINICAL PRACTICE 9
REV IEW / DNA variants of cats
Breed/Family Place founded Derived breed/grouping*Abyssinian India? Somali
American Bobtail Natural mutation United States – random breds
American Curl Natural mutation United States – random breds
American Shorthair United States American Wirehair
American Wirehair Natural mutation American Shorthair
Peterbald Mutation Russian – random breds, Don Sphynx
Pixie-bob Crossbreed hybrid Manx, Japanese Bobtail, United States – random breds
Ragdoll United States United States – random breds
Russian Blue Europe
Savannah Species hybrid Serval × domestic
Scottish Fold Natural mutation United Kingdom – random breds, British SH, Persian
Selkirk Rex Natural mutation United States – random breds, Persian
Siamese Southeast Asia Balinese, Havana Brown, Javanese, Colorpoint, Oriental
Siberian Europe Russian – random breds
Singapura Variant Bombay, Burmese, Tonkinese
Sokoke Arabian Sea African – random breds
Somali Variant Abyssinian
Sphynx Natural mutation Devon Rex
Tonkinese Variant Bombay, Burmese, Singapura
Turkish Angora Mediterranean
Turkish Van Mediterranean
*Modified from genetic studies based on 29 tetranucleotide short tandem repeat markers, 39 dinucleotide shorttandem repeat markers, and unpublished data (LA Lyons)
Table 4 Genetic families of domestic cat breeds
By consideringthe breed
relationships in Table 4,
genetic healthconcernsacross catpopulations
and breeds canbe inferred dueto inheritance
viaoutcrossing.
10 JFMS CLINICAL PRACTICE
REV IEW / DNA variants of cats
And the ‘ugly’ cat variants – be careful with selection
To date, most cat genetic tests have been fortraits that have nearly complete penetrance,have little variability in expression and haveearly onset. However, some recognized dNAvariants in cats might be considered risk fac-tors, predisposing an individual to a specifichealth problem. Hence, these traits are notclean and clear, simple genetic traits, but com-plex risk factors and susceptibilities with‘ugly’ genetics. Unfortunately, a majority ofthe variation in the genome will prove to bemodifiers, polygenes that have dNA variants
with small heritable effects. To date, researchhas focused on the simple genetic traits incats, which is just the tip of the iceberg.deciphering ‘ugly’ genetic variation is thefuture.
The reasons as to why a condition wouldnot present when a specific dNA variant ispresent have been predicted and are nowbeing deciphered as we understand more andmore about our entire genomic sequence.Environmental interactions certainly play arole in the overall appearance and health of anindividual and its organs. Several knowngenetic mechanisms can make dNA variantsmore difficult to interpret and to predict theirconsequences.
Vitamin D Resistant Rickets108 000837-9685 CYP27B1 c.223G>A, c.731delG
Vitamin D Resistant Rickets109 000837-9685 CYP27B1 c.637G>T
*The presented conditions are not prevalent in breeds or populations but may have been established into research colonies. †Not all transcripts for a given gene may have been discovered or well documented in the cat, mutations presented as interpreted from original publication. ‡A variety ofmutations have been identified, yet unpublished for porphyrias in domestic cats. Contact PennGen at the University of Pennsylvania for additionalinformation. OMIA: Online Mendelian Inheritance in Animals (http://omia.angis.org.au/home/) entries provides links to citations and clinicaldescriptions of the phenotypes and the diseases. Presented citations are for the causative variant discovery
Table 5 Uncommon mutations for inherited domestic cat diseases*
JFMS CLINICAL PRACTICE 11
REV IEW / DNA variants of cats
< Incomplete penetrance – for some traitsand diseases, even though a knowncausative variant has been identified, anindividual with that variant does notpresent with the condition.
< Age of onset (age-related penetrance) –some diseases have a slow progression andmay not develop until later in life.Basically, the cat needs to be monitored fora long period to determine if a carrier foran undesired trait, or clear of the disease.
< Variable expression – most traits anddiseases have some amount of variableexpression depending on the individual.Some cats with PKd have only a few cystsand never progress to kidney disease,others have severe and fast progression ofdisease and succumb to renal failure earlyin life.
< Disease heterogeneity – often, more thanone variant in the same gene, or variants indifferent related genes can cause the samedisease. Genetic heterogeneity for HCM inhumans is well established, thus, there isno reason to not think the same situation istrue for cats.
< Genetic testing accuracy – even though aspecific genetic variant may be identifiedfor a genetic trait or disease, researchlaboratories use different methods to assayfor the variant. Errors in genetic assaysmay produce inaccurate dNA results,leading to the confusion of genetic testinterpretation.
< Inaccurate clinical diagnosis – As in thegenetic laboratory, standard proceduresand definitions, equipment sensitivity, andtraining of the veterinary technician andtheir experience all affect accuratediagnoses.
An excellent example of a variant that con-fers a risk in cats is the dNA variant associat-ed with cardiac disease in cats. Hypertrophiccardiomyopathy (HCM) is a recognizedgenetic condition.110 in 2005, drs Meurs,Kittleson and colleagues published that a pro-tein alteration, A31P, in the gene for cardiacmyosin-binding protein C 3 (MYBPC3) wasstrongly associated with HCM in a long-termresearch colony of Maine Coon cats at theUniversity of California – davis.74 The dataclearly showed not all cats with the varianthad HCM and some cats with HCM did nothave the dNA variant. Age of onset, variableexpression, and disease heterogeneity werediscussed in this report. These confoundingfactors suggested that the identified dNAvariant should to be considered more of a ‘riskfactor’ than a directly causative variant.Recent studies have shown that not all MaineCoon cats with the A31P variant get HCM111,112
and one of those papers has mistakenly inter-
preted this lack of penetrance as being evi-dence that the A31P variant is not causal.112
This interpretation is misleading, causingdebate as to the validity of the Maine CoonHCM test. As true in humans with cardiac dis-ease, the finding that not all cats with theA31P variant in MYBPC3 get HCM is actuallyusual in the field of HCM genetic testing. Thecontroversy led to discussions within the jour-nals and continued studies to clarify the inter-pretations.113 Also, an additional variant inMYBPC3, known as A74T was suggested at ascientific meeting as causative for HCM.When some commercial testing laboratoriesstarted offering the A74T test to the cat com-munity, it became evident that A74T was apolymorphism occurring in a large number ofbreeds, not significantly correlated to HCM,and that A31P penetrance was incomplete buthighly associated with disease.114
Like cat HCM variants, other disease vari-ants have shown variation in penetrance andexpression. The CEP290 PRA variant inAbyssinians has a late age of onset and somecats with subclinical disease have been identi-fied.115 Some cats with the pyruvate kinasedeficiency can have very mild and subclinicalpresentations.116 Thus, disease or trait causingvariants may not be 100% penetrant, notalways causing clinically detectable disease.
Cats are one of the few species to have thevariant for their blood type determined. Bloodtype incompatibilities can lead to transfusionreactions and neonatal isoerythrolysis for thecat, but inherently this characteristic is notnecessarily a disease. A point mutation and an18 base pair deletion have both been implicat-ed in the gene CMAH as indicating the pres-ence of the B blood type, or a B blood type car-rier.70 Because both variants are on the sameallele, a clear indication of the true causativevariant has not been determined. Thus, at thecurrent time, both variants should be exam-ined in cats to genetically determine bloodtype and some laboratories have been identi-fied that are not only typing the incorrect variant, but also not both variants. Breedersgenerally are the first to recognize when agenetic testing laboratory is making errors.Laboratories associated with research groupsare most likely to correct errors and performfurther studies to improve their testing accu-racy.
Several cat breeds were formed by crossingwith different species of cats. The Bengalbreed is acknowledged worldwide and hasbecome a highly popular breed. To createBengals, Asian leopard cats were and are bredwith Egyptian Mau, Abyssinian and other catsto form a very unique breed in both color andtemperament.117 The Chausie is developingfrom crosses with Jungle cats, and Savannahs
12 JFMS CLINICAL PRACTICE
REV IEW / DNA variants of cats
from crosses with Servals. Bobcat hybrid catshave not been genetically proven to date. AnAsian leopard cat had a common ancestorwith the domestic cat about 6 million yearsago, the bobcat about 8 million years ago andthe Serval about 9.5 million years ago.118 TheJungle cat is more closely related to a domesticcat than the leopard cat to the domestic cat. inaddition, for some of these wild felid species,different subspecies were incorporated intothe breed. The dNA sequence between adomestic cat and one of these wild felidspecies will have many genetic differences,maybe a several percentage difference, less forthe Jungle cat, more for Serval as comparedwith a domestic cat. The genetic differencesare most likely silent (neutral) variants, but,the variation will interplay with geneticassays and may cause test failures or inaccura-cies than what would be normally anticipated.No genetic tests are validated in the hybridcats breeds, although the tests are typicallyused very frequently in Bengal cats. Thus, theaccuracy for any genetic test is not known forhybrid cat breeds. A simple example in thecharcoal coloration in the Bengal cat.119 Thiscoloration is due to the cats having one allelefrom the leopard cat, APbe, for Agouti and theirsecond allele in the domestic cat non-agouti, a.if Bengal cats can have alleles from differentspecies for color, they have a possibility of dif-ferent alleles at all other genes in their genomeas well.
Parentage testing, individual,breed and race identification
Standardized genetic tests are important forsharing information, combining datasets andassisting with population management. Peer-review, research collaborations, and forumsand comparison tests hosted by theinternational Society of Animal Genetics(iSAG) allow both formal and informal over-sight of parentage test development in domes-ticated species. Under the auspices of iSAG, amicrosatellite-based dNA profiling panel forparentage and identification in the domesticcat120 has been developed and vetted by 17worldwide commercial and research laborato-ries. Nine microsatellite dNA markers andtwo additional gender markers are sufficientfor parentage, gender determination, andidentification testing of random bred, pure-bred and several wild felid species. Althoughno cat breed registry makes use of this tech-nology to prove the accuracy of pedigrees, theopportunity does exist and is offered by labo-ratories around the world.
A newly developed test for the domestic catis a race and breed identification panel, a CatAncestry panel. Based on the studies by
Lipinski et al121 and Kurushima et al,122
microsatellites (aka short tandem repeats[STRs]) and single nucleotide polymorphisms(SNPs) have been tested in a variety of ran-dom bred cats from around the world and amajority of the major cat breeds of the USAand other regions. The genetic studies havebeen able to differentiate eight worldwidepopulations of cats – races – and can distin-guish the major breeds. Many cat breedsshould be considered as genetic family groups(Table 4). Phenotypic markers help to delin-eate breeds within specific breed families,such as the Persian, Burmese and Siamesefamilies. For example, the fold dNA variant ofa Scottish Fold will demarcate an individualin the Persian family as being a Scottish Foldand not an Exotic Shorthair. The cat race andbreed identification tests are similar to teststhat have been developed for the dog.Although similar, domestic cats are from random bred cat populations and not a con-coction of pedigreed breed cats. Cat breedsdeveloped from the random bred popula-tions, which existed in different regions of theworld for thousands of years. Therefore, mostrandom bred cats will match to a regionalpopulation of cats, a ‘race’ of cats, and not to amixture of different breeds. Many feral dogsare actually bred mixes, not true with cats.The feral cat populations existed long beforethe breeds and the breeds are sub-sets of thegene pools of feral cat populations.
Whole genome sequencing forfeline health care
dNA testing for domestic cat diseases andappearance traits is a rapidly growing assetfor veterinary medicine. A variety of commer-cial laboratories can now perform cat geneticdiagnostics (Table 3), allowing both the veteri-nary clinician and the private owner to obtaindNA test results. dNA is easily obtained froma cat via a buccal swab using a standard cot-ton bud or cytological brush, allowing dNAsamples to be easily sent to any laboratory inthe world. The dNA test results identify carri-ers of the traits, predict the incidence of traitsfor breeding programs, and influence medicalprognoses and treatments. Besides controllingthe occurrence of disease, one long-term goalof identifying these genetic variants is the cor-rection of the defect via gene therapies anddesigner drug therapies. Thus, genetic testingis an effective preventative medicine and apotential ultimate cure by selective breeding.However, genetic diagnostic tests may still benovel for many veterinary practitioners andtheir application in the clinical setting needsto have the same scrutiny as any other diag-nostic procedure.
JFMS CLINICAL PRACTICE 13
REV IEW / DNA variants of cats
Genetic testing has been a part of modernhealth care since the national implementationof the dNA mutation test for phenylketonuria(PKU) in the 1960s.123 Most individualhumans in the USA do not realize that, atbirth, after a heal prick blood collection, theywere tested for a battery of genetic diseases.Similar testing is now available to the publicas an elective evaluation of a person’sgenome. Companies, such as 23andMe(www.23andme.com), offer a personal genet-ics service that presents your own variants forknown single gene traits and also variantsthat confer risk. Similar offerings are availablefor domestic cats. However, genetic servicesmust be careful to not be replacing the role ofthe clinician or veterinarian, since the inter-pretation of the genetic results should bemade by a professional as part of an overallhealth care plan. Many laboratories, such asthe University of California – davis(www.vgl.ucdavis.edu), offer both a majorityof the genetic tests important for cat breedsand also a Cat Ancestry test that can deter-mine your cat’s race and potential breed.However, in both humans and hopefully cats,the future of individual health care will relyon the individual’s personal genome.
A result of the Human Genome Project hasbeen the development of rapid and cost effec-tive means to sequence an entire genome of anindividual in less than one month. Currently,whole genome sequencing is becoming thestandard of health care for genetic profiling ofcancers, which can dictate the proper selectionof chemotherapies based on dNA mutationsof the tumor.124 At specialized centers aroundthe world, newborns with sporadic, congeni-tal abnormalities can be whole genomesequenced, which often, but not always,detects the cause of their maladies.125 Since
over 100,000 people have now had theirgenomes sequenced, the database of normaland detrimental genetic variants is fairly welldefined in some human populations butrequires greatly better definition in others.126
Likely, whole genome sequencing willbecome part of the health care package forhuman health.127 Recently, the $1000 genomecost has been reached for humans, shortly thistechnology will be adapted for otherspecies.128 For cats, currently whole genomesequencing is being used to investigate dis-eases and traits that are known to be heritableand when sufficient individuals are not avail-able for a different means of genetic analysis,such as family studies or case-control associa-tion studies. Like humans, eventually, thegenetic variant databases will be sufficient forthe analysis of an individual cat with anunusual health presentation. The 99 Lives CatGenome Sequencing initiative (http://feline-gene tics.missouri.edu/ninety-nine-lives) hasbeen launched to meet the same standard inhealth care for cats as for humans. The spo-radic or idiopathic conditions will slowly bedetermined to have individual specific geneticcauses, leading to highly specific personalizedmedicine for our companion animals.
Funding
This work was supported in part by funding fromthe National Center for Research Resources R24RR016094 and is currently supported by the officeof Research infrastructure Programs/odR24od010928.
Conflict of interest
The author declares that there is no conflict of inter-est.
< Genetic testing is an important diagnostic tool for the veterinarian, breeder and owner.
< Genetic tests are not 100% foolproof and the accuracy of the test procedure and the reputation and customerservice of the genetic testing laboratory needs to be considered.
< Understanding the relationship of cats to the race of origin and their breed families can be predictive for healthcare issues.
< Some traits are highly desired and genetic testing can help breeders to more accurately determine appropriatebreedings, potentially becoming more efficient breeders, thus lowering costs and excess cat production.
< Other traits or diseases are undesired; thus genetic testing can be used to prevent disease and potentiallyeradicating the concern from the population.
< Genetic tests for simple genetic traits are more consistent with predicting the trait or disease presentation, but, as genomic research progresses for the cat, more tests that confer risk will become more common.
< Veterinarians will have to consider the weight of a risk conferring disease variant as part of their differentials and treatment plans and breeders will have to consider these same risk factors along with the other important attributes of a cat for their breeding decisions.
KEY POINTS
14 JFMS CLINICAL PRACTICE
REV IEW / DNA variants of cats
References
1 Lyons LA. Feline genetics: clinical applications and genetic test-
ing. Top Companion Anim Med 2010; 25: 203–212.
2 Lyons LA. Genetic testing in domestic cats. in: August JR (ed).
Consultations on feline internal medicine. St Louis, Mo: Saunders