Molecular genetics of familial hypertrophic cardiomyopathy

Familial hypertrophic cardiomyopathy (FHC) is a genetically and phenotypically heterogeneous disease with an autosomal dominant Mendelian inheritance. Mutations in four different genes coding for sarcomeric proteins have been identified to cause the disease. In 1990, a mutation in the beta-myosin heavy chain (beta MHC) gene was identified to cause familial hypertrophic cardiomyopathy. Soon after, more than 30 missense mutations and one deletion in the beta MHC gene were identified to be responsible for FHC. This was followed by mutations in troponin T, alpha tropomyosin and cardiac myosin binding protein-C genes. In patients with familial hypertrophic cardiomyopathy due to beta MHC mutations, the mutant beta MHC mRNA and protein have been isolated from cardiac and skeletal muscle of these individuals. Functional studies have shown that the mutant beta MHC protein has impaired actin-myosin interaction and expression of the mutant beta MHC in feline cardiocytes disrupts the assembly of the sarcomere. Similarly, mutations in the other three genes lead to mutant proteins which interfere with the normal structure and function of the sarcomere, resulting in an identical phenotype of sarcomere disarray, the hallmark of FHC.