Single Cell Transcriptomic Profiling of MYBPC3-Associated Hypertrophic Cardiomyopathy Across Species Reveals...

Hypertrophic cardiomyopathy (HCM) is a common heritable heart disease where the most frequently associated mutations occur in the myosin-binding protein C (MYBPC3) sarcomere-associated gene. HCM is also a common veterinary clinical problem in certain cat breeds such as Maine Coons and Ragdolls, also most associated with mutations in MYBPC3. Mouse models of HCM in which Mybpc3 mutations are introduced recapitulate some, but not all, features of human HCM.

To elucidate the common and distinctive pathological pathways across species and foster a greater understanding of the concordance of mouse HCM models to clinical mybpc3-associated HCM, we generated single nuclei RNA-sequencing data sets from feline, human, and murine heart tissue carrying MYBPC3 variants. Numerous genes were differentially expressed between mutation positive and mutation negative cell types within each species, identified using the model-based analysis of single-cell transcriptomics algorithm. Gene Ontology enrichment analysis of differentially expressed genes in cardiomyocytes across species revealed alterations in genes involved in muscle development, muscle contraction, muscle hypertrophy, regulation of sarcoplasmic calcium release, ATP metabolic process, and oxidative phosphorylation.

These common biological processes across species are consistent with known phenotypic aspects of HCM such as hypertrophy, hypercontractility, diastolic dysfunction, and altered energy metabolism. Surprisingly, among conserved biological processes within cardiomyocytes across species, the individual genes driving the biological processes were distinct. This work to identify common and species-specific disease-promoting pathway differences will allow development of targeted therapies for both human and veterinary application and will facilitate an understanding of the idiosyncrasies of mouse models.