Inherited Diseases of Domestic Cats

Leslie  A.  Lyons,  PhD  Professor  

 Popula5on  Health  &  Reproduc5on  School  of  Veterinary  Medicine  University  of  California,  Davis  

Lalyons@ucdavis.edu  (530)  754-­‐5546  

 

Genetic Distinction of Breeds

23 of 26 breeds distinct - Persian = Exotic - Siamese = Havana Brown - Scottish Fold = British Shorthair

Questions to decipher inheritance?

  Is the diagnosis accurate and consistent?   Have you seen the condition before?   Has it been seen in this breed before?   How common is it?   How many breeding animals within the breed?   Has it been seen in other breeds before?   Has it been seen in other species before?   What is the breeding?

Hallmarks of Genetic Conditions

 Bilateral presentation

 Consistent presentation

  “Early” onset  Species specific  Disease dependent

 Advanced parental age?

Common Misinterpretations

 Familial is not always clearly heritable due to the environmental component

 Congenital is not always heritable due to the environmental component

 Don’t forget random chance (idiopathic)

Cat Disease Mutations •  33 genes in cats

–  51 mutations •  37 phenotypes

•  10 genes colors / traits –  16 breed mutations

•  13 phenotypes –  1 polydactyla = AD

  14 mutations offered my VGL   Not SHH for Pd   ? Full albino mutation

Genetic Diseases in Cat Breeds Breed   Sister  /  Family  Group   Disease  -­‐  Gene  

Abyssinian   SOM,  OCI,  BEN,  SIA…   PRA  (blindness)  –  CEP290  

Abyssinian   SOM,  OCI,  BEN,  SIA…   Pyruvate  Kinase  Def  -­‐  PKLR  

Burmese   BLM,  Bombay,  Singapura,  Tonkinese   GM2  –  HEXB  

Burmese   BLM,  Bombay,  Singapura,  Tonkinese   Hypokalemia  –  To  be  named  

Burmese   BLM,  Bombay,  Singapura,  Tonkinese   Craniofacial  –  To  be  named  

Korat   SIA…   GM1  –  GLB1  

Korat   GM2  -­‐  HEXB  

Maine  Coon   HCM  –  MYBPC3  (A31P)  

Maine  Coon   Spinal  Muscular  Atrophy  –  LIX1/LNPEP  Maine  Coon   Polydactyla  -­‐  SHH  

Norwegian  Forest   Glycogen  Storage  –  GBE1  

Persian   EXO,  BRI,  ASH,  BLM,  Selkirk  Rex   Polycys5c  Kidney  –  PKD1  

Pixiebob   Polydactyla  -­‐  SHH  

Ragdoll   HCM  –  MYBPC3  (R820W)  

Cat Coat Color & Type Tests Trait   Gene   Alleles  -­‐  MOI   Notes  

Agou5   ASIP   A+  >  a  

Brown   TYRP1   B+  >  b  >  bl  

Color   TYR   C+  >  cb  =  cs  >  c  

Dense  (Dilute)   MLPH   D+  >  d  

Extension  (Amber)   MC1R   E+  >  e  

Gloves  (Birman)   KIT   G+  >  g  

Hairless  (Sphynx)   KRT71   Hr  >  hr+  >  re  

Long  hair   FGF5   L+  >  l   4  muta5ons  

Polydactla   SHH   Pd  >  pd+  

Rex    (Devon  Rex)   KRT71   Hr  >  hr+  >  re  

Rex  (Cornish  rex)   P2RY5   R+  >  r  

Sex   AMEL,  XFXY   X,  Y  

+ Indicates the wildtype, normal allele

Hybrid Cat Breeds

Leopard Cat - Bengal

Serval - Savannah

Jungle Cat - Chaussie

F1 Bengal Cat

Female DSH

2N = 38 2N = 38

•  Normal tortie/calico •  Male genitalia •  Normal chromosomes

–  Unknown abnormality •  Sterile

–  Unknown cause

Tortoiseshell Males - Sterility

Feline PKD

Persian family, 1969   Exotics, Himilayan

Renal Cysts   Hepatic cysts

Clinically Consistent   Varies in severity Early Onset

  8 months ultrasound Single Gene   Autosomal Dominant

Polycystic Kidney Disease Pathology

Progressive chronic tubulointerstitial nephritis in cats with ADPKD

3 months old 3 years old

Slides courtesy of S. DiBartola

Variation in PKD

Ultrasound image of PKD

Feline AB Blood Group

•  Recognized since 1915

•  Anti-sera developed by Auer & Bell, early 1980’s: A, B, and AB

•  A > B, not sure about AB

•  Transfusion reactions

•  Neonatal isoerythrolysis –  B have strong anti-A

NeuGC Biosynthetic Pathway

CMP-Neu5Ac synthetase

(CMAS)

In the nucleus

In the cytoplasm

(CMAH) Key enzyme:

•  humans don’t have NeuGc due to a 92 bp deletion of the gene

critical activation

Bighignoli et al., BMC Genet. 2007: 8:27

Breed Country Cats A% B% AB% Abyssinian US34 230 86.5 13.5 0 Abyssinian US33 194 79.9 20.1 0 Birman US33 216 82.4 17.6 0 British Shorthair UK42 121 39.7 58.7 1.6 British Shorthair US3 85 41.2 58.8 0 British Shorthair Germany37 33 54.5 45.5 0 Burmese Australia48 30 93 3 3 Burmese US33 25 100 0 0 Chartreux Germany50 27 77.8 18.5 3.7 Devon Rex US34 288 50.3 49.7 0 Devon Rex US33 100 57 43 0 Devon Rex* Australia48 71 45 54 1.4 Maine Coon Germany50 25 96 4 0 Persian US34 230 90.4 9.6 0 Persian US33 170 75.9 24.1 0 Persian Germany37 157 91.7 7.6 0.6 Ragdoll Italy53 36 72.2 8.3 19.4 Scottish Fold US33 27 85.2 14.8 0 Siamese US33 99 100 0 0 Siamese Italy35 26 96.2 3.8 0 Turkish Angora Turkey45 28 53.6 46.4 0 Turkish Van Turkey45 85 40 60 0

Breed Blood Type Frequencies

Pyruvate Kinase Deficiency

"   Red cell disorder found in many species

"   an inherited lack of the enzyme pyruvate kinase, which is used by red blood cells

"   red blood cells break down too easily, resulting in low levels of these cells (hemolytic anemia)

Pyruvate Kinase Deficiency

Symptoms •  Anemia •  A yellowing of the whites

of the eyes (icterus) •  Fatigue, lethargy •  Jaundice •  Pale skin (pallor)

Signs & Tests •  Bilirubin in the blood •  CBC •  mutation in the pyruvate

kinase gene •  Large red blood cells

(macrocytosis) •  Levels of haptoglobin in the

blood •  Osmotic fragility •  Pyruvate kinase activity •  Stool urobilinogen

Feline Retinal Degeneration

•  Abyssinian family •  Bilateral Rod-Cone

Degeneration •  Clinical Consistent •  Late Onset

– Slow Progression 1-2 yrs •  Single Gene

– Autosomal Recessive – Complete Penetrance

•  Narfstrom et al. 1983

Feline Retinal Degeneration

•  Abyssinian family •  Bilateral Rod-Cone

Dysplasia •  Clinical Consistent •  Early Onset

– Fast Progression 8 wks •  Single Gene

– Autosomal Dominant – Complete Penetrance

•  Keith & Ross, 1985

Feline Retinal Degeneration •  Persian family •  Bilateral •  Clinical Consistent •  Early Onset

– Fast Progression: 8-16 wks •  Single Gene

– Autosomal Recessive – Complete Penetrance

•  Rubin & Lipton, 1973 – Aguirre, Lyons

Persian PRA Color Fundus Examination

Affected Male

Affected Female

Unrelated Normal

Carrier

Persian PRA Angiography

Normal

Affected

Structure of the eye

Light

(Bessant et. 2001)

(PetEducation.com)

Affected

Carrier

Control

3 weeks 5 week 7 weeks 16 weeks

Figure 2. Histological morphology of retinas from PRA-affected, carrier and control cats

Persian PRA

Frequency CEP290 •  16/43 (37%) breeds, exhibiting a high allele frequency

(∼33%) in North American and European Siamese populations.

Abyssinian/Somali (USA) 16 0.070 0.005 Abyssinian (UK) 34 0.206 0.042 Abyssinian (Australia) 57 0.105 0.011 Abyssinian (Scandinavia) 130 0.196 0.038 American curl 10 0.050 0.003 American wirehair 10 0.100 0.010 Bengal 18 0.056 0.003 Balinese/Javanese 24 0.333 0.111 Colorpoint shorthair 11 0.364 0.132 Cornish Rex 20 0.025 0.001 Munchkin 15 0.033 0.001 Ocicat 18 0.083 0.007 Oriental shorthair 25 0.340 0.116 Siamese 49 0.265 0.070 Singapura 6 0.167 0.028 Tonkinese 7 0.071 0.005

N Observed hetero Expected affected

Korat – Gangliosidosis

•  Autosomal Recessive •  GM1 Gangliosidosis

–  GALB –  17.4% carrier frequency

•  GM2 Gangliosidosis –  HEXB –  6.2% carrier frequency

•  similar clinical & pathological characteristics

•  Scott-Ritchey Research Center

GSD IV Phenotypes •  autosomal recessive •  Neuromuscular degeneration

–  Cardiac failure •  Most affected kittens are stillborn or die within

hours of birth. •  A few affected kittens survive the perinatal

period –  Clinical signs at 5 mos –  Complete debilitation by 8-10 mos

Feline GSD IV GBE Gene

Rearrangement and 6.1 kb Deletion

2 kb 4 kb 6 kb 8 kb

Eco RI Eco RI Eco RI

A

N (CA) Rep

Burmese Hypokalemia

!

  Gruffydd-Jones 1986

  Non-USA Burmese cats

  Autosomal recessive

  Metabolism disorder causes low potassium

  Seizures, generalized muscle weakness

  Can be managed with supplements

Youtube – Gordon - Burmese

Burmese Head Defect

•  Burmese Family –  Contemporary style

•  Autosomal Recessive –  Carriers undetectable

•  Congenital/Lethal

•  Duplication of Upper Maxillary

•  Proper Counseling

Burmese Head Defect

Burmese Head Defect

Feline HCM Risk Factors

"   Breed and lineage history "   Common environment "   Male cats "   Having two copies of the mutations

(homozygote) "   Maybe having two of either mutation?? "   Increased age, male

Feline HCM Genetics

"   Most HCM in humans is Autosomal Dominant with variable penetrance

"   Over a dozen genes cause HCM, including Myosin-binding protein C (MBPC3)

"   Mutations in MBPC3 in Maine Coon and Ragdoll indicate high risk for HCM

Genetic Counseling for HCM

"   Reduce breed or lineage risk

"   Use genetic testing

"   Combine with ultrasound diagnosis

"   Do not breed homozygous cats or cats with severe HCM that are young