The Polysaccharide Storage Myopathy Phenotype in Quarter Horse-Related Breeds is Modified by an RYR1 Mutation
ACVIM 2008
M.E. McCue; S.J. Valberg; M. Jackson; M. Lucio; L. Borgia; J.R. Mickelson
University of Minnesota, College of Veterinary Medicine
St. Paul, MN, USA

A dominant mutation in the GYS1 gene causes one form of Polysaccharide Storage Myopathy (PSSM) in Quarter Horses. Horses with the GYS1 mutation have a variable clinical phenotype ranging from subclinical disease to exertional rhabdomyolysis, to acute recumbency and death. Variable phenotypic expression may be attributed to environmental factors such as diet and exercise as well as modifying genes. We have identified one family of GYS1 PSSM horses with a severe and occasionally fatal PSSM phenotype. The purpose of this study was to determine if a modifying gene(s) contributes to phenotypic variability of severely affected PSSM Quarter Horses and related breeds.

A severely affected GYS1 PSSM family was selected for study from 3 families used in a whole genome association study to identify the GYS1 mutation. The genotypes from these families and additional GYS1 PSSM horses were re-evaluated after identification of the GYS1 mutation. Our goal was to identify loci that were highly associated with the PSSM phenotype in the severely affected family, but not associated with the PSSM phenotype in the other 2 PSSM families. A microsatellite marker was found on ECA10 that met this criteria (p=0.000072 severely affected family; p=0.3 horses outside this family). The microsatellite marker was approximately 2 Mb from the RYR1 gene leading to the hypothesis that a mutation in RYR1, previously reported to cause malignant hyperthermia (MH) in Quarter Horses, was modifying the GYS1 phenotype. Horses in the severely affected family, 203 additional Quarter horses heterozygous for the GYS1 mutation and hair root samples from 330 randomly selected Quarter horses were genotyped for the RYR1 mutation by restriction fragment length polymorphism assay. Of the 44 horses with the GYS1 mutation within the severely affected family, 26 had the MH mutation (59%). In contrast, the prevalence of the MH mutation in horses heterozygous for the GYS1 mutation outside the family was 1.5% and in randomly selected horses 0.6%. From this data we hypothesized that the MH mutation in combination with the GYS1 mutation was responsible for a more severe phenotype. To test this hypothesis, serum creatine kinase (CK) data were evaluated from 9 horses with the GYS1 mutation, 4 of which also had the MH mutation. CK activity was determined 4 h after exercise for 15 days while horses consumed a high starch diet. Mean CK activity was significantly higher (t test p<0.0001) in horses with both MH and GYS1 mutations (3591±720 U/L compared to 1584 ±220.5 U/L).

In conclusion, although the phenotype of horses with the GYS1 mutation is influenced by diet and exercise, it may also be modified by the presence of the RYR1 MH mutation. Therefore, in Quarter Horses and related breeds it may be prudent to test for both these mutations.

Speaker Information
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Molly McCue, DVM, MS, PhD, DACVIM
Department of Vet Population Med
St. Paul, MN

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