The Maine Coon Cat Harboring the MYBPC3-A31P Mutation: A Genotype-Stratified Phenotypic Characterization of Hypertrophic Cardiomyopathy

Abstract

Background Most animal models of HCM are mouse-based, but the thin interventricular septum in mice makes it difficult to clearly distinguish pathological hypertrophy, which introduces substantial errors and constrains basic HCM research. Cats develop HCM spontaneously, and the common MYBPC3-A31P variant in cats is homologous to human mutations in both genetics and pathology, with a larger body size that makes them suitable as large-animal models. This study examines how heterozygosity or homozygosity for the p.A31P mutation (c.91G>C) in the MYBPC3 gene affects the phenotype and severity of HCM in affected cats, with the aim of establishing an ideal large-animal model for clinical risk stratification and precision diagnosis and treatment of human HCM. Methods Forty-nine Maine Coon cats were enrolled and stratified into homozygous mutant (HOM, n=8), heterozygous mutant (HET, n=26), and wild-type (WT, n=15) groups. All cats underwent echocardiography, blood pressure measurement, physiological assessment, hematological and biochemical analyses, and cross-species sequence conservation analysis. Results No significant differences in baseline characteristics including age and body weight were observed among groups (P>0.05). HOM cats exhibited significantly higher left ventricular outflow tract pressure gradients and greater basal septal thickness compared to WT cats (P<0.05), with HET cats showing intermediate values. Analysis of hematological and serum biochemical parameters revealed no evidence of systemic inflammation or hepatic injury. Sequence conservation analysis confirmed that the A31 residue is highly conserved across mammalian species. Conclusions This study provides a phenotypic characterization of Maine Coon cats carrying the MYBPC3-A31P mutation, revealing marked gene-dose effects on cardiac structure and function, with homozygous individuals exhibiting more severe phenotypic features. This model serves as a large-animal translational platform that not only clarifies genotype–phenotype correlations but also supports risk stratification and precision therapeutic strategies in human HCM. Its spontaneous nature and genetic homology to human disease make it particularly valuable for bridging preclinical findings to clinical application. RESEARCH PERSPECTIVE What Is New? This study provides a genotype-stratified phenotypic characterization of MYBPC3-A31P mutation in Maine Coon cats, covering echocardiographic and laboratory parameters across homozygous, heterozygous, and wild-type groups. The results suggest a gene-dose effect, with homozygotes showing more pronounced cardiac changes, heterozygotes showing intermediate features, and wild-types remaining unaffected. All cats were raised under uniform environmental and dietary conditions, which may reduce the confounding effects of extrinsic factors compared with studies using cats from varied sources. What Question Should Be Addressed Next? Longitudinal follow-up of this cohort could help determine whether the observed genotype-related differences progress to clinical events over time. Protein-level and functional studies would be useful to explore the molecular mechanisms underlying the gene-dose-dependent phenotype. The utility of this feline model for evaluating genotype-specific therapeutic approaches remains to be examined.