Mutational Analysis of Four Sarcomeric Genes in Three Breeds of Cats with Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is an inherited disease in the Maine Coon (MC) and Ragdoll (RD) breeds. It is thought to be inherited in the Norwegian Forest Cat (NWF) and British Shorthair (BS) as well. We have previously identified two unique causative mutations in different regions of the myosin binding protein C (MYBPC3) gene in the MC and RD breeds. However, not all affected MC and RD cats with HCM have their known mutation and neither of these mutations has been identified in affected NWF or BS. Genetic heterogeneity has been observed in human HCM and > 400 mutations have been identified, most commonly in one of 8 sarcomeric genes.
We hypothesized that a mutation in one of a select set of sarcomeric genes (MYBPC3, ß-myosin heavy chain (MYH7), troponin I (TNI), essential myosin light chain (MYL3)) would be associated with the development of HCM in each of NWF and BS cats and MC cats with HCM but without the known MYBPC3 mutation (A31P). PCR based sequencing of all exonic and splice site regions for these 4 genes was performed with DNA samples from three affected cats from each breed. The resulting sequencing data were compared to the corresponding sequence for all genes in 2 control cats and the published normal feline sequence. Base pair changes were considered to be causative for HCM if they met the following criteria: were present in at least some of the affected cats but not in the controls, changed a conserved amino acid and changed the amino acid to one of a different polarity, acid/base status or structure.
No significant differences were observed within the exonic and splice site regions of these genes between the affected cats and the control cats or the published feline sequence. Several polymorphisms were observed within each gene but did not segregate with disease or change the amino acid.
Since causal sarcomeric mutations have been previously identified in two breeds it is anticipated that other mutations will be identified in other breeds. This study ruled out causative mutations in the 4 genes from representative cats from these three breeds. Additional studies with other sarcomeric genes and other breeds are warranted.