Prevalence of MYBPC3 gene mutations and association with hypertrophic cardiomyopathy in several cat breeds

Pure breed cats are a useful model in inherited disease study due the specific knowledge of population genetic and accurate genealogical data often tracing back to the foundation stock of the breed.Furthermore high conservation rates with human and domestic animals genomes are well known. The aim of this work was to examine the Maine Coon (MC) and Ragdoll (RD) HCM-associated MYBC3 known mutations in a large sample of cat breeds, and to investigate the genotype-phenotype association. An in silico evaluation of the impact of the amino-acid (aa) substitutions was carried out. 762 cats (MC, RD and other 9 breeds) were genotyped at loci A31P and R820W, cats were examined with echocardiography (Osservatorio Italiano HCM Felina). Prevalence of the clinical form in all breeds and Odd Ratio to evaluate the disease risk in mutant allele/s carriers in MC were determined. The potential impact of the aa substitutions was simulated using Modeller 9v8 and the human MYBPC3 as template. Data strongly confirm A31P (all.freq. 0.23) and R820W (all.freq. 0.17) as private mutations of MC and RD respectively. In MC significant differences (P<0.001) were recorded in the genotypic frequency of mutant A31P homozygous between healthy and affected (OR 9.5, CI 4.9-65.7). Functional modeling predicted the potential ability of A31P to perturb the overall fold and stability of the protein. However the heterozygous status is not fully associated with HCM, suggesting a not complete dominance and other mechanisms involved in HCM developing.These data will help the cat breeders to understand HCM genetic test results and to drive their selective choices.