Molecular genetics of familial hypertrophic cardiomyopathy

Familial Hypertrophic Cardiomyopathy is the first inherited primary cardiomyopathy for which genetic studies have been conducted. It is an autosomal dominant inherited disease, and represents an important cause of sudden death particularly in otherwise healthy young individuals such as athletes. The first chromosomal locus has been mapped on chromosome 14 at q11-q12 where the putative gene is that encoding beta-myosin heavy chain. Several missense mutations have been identified in this gene, almost all of them are located in the region coding for the globular head of the molecule, and codon 403 is a hot-spot for mutations. Mutant alleles are expressed in both cardiac and skeletal muscles of patients where histological studies showed that gross alterations in myosin assembly do not occur. However in vitro experiments strongly suggest that mutant myosins have an impaired ability to form filaments and to interact with actin. The exact mechanisms by which myosin mutations cause FHC are not known. Very recently, three novel chromosomal loci for FHC have been identified on chromosomes 1q3, 11p13-q13, and 15q22. The challenges for the future are the identification of the other genes causing FHC, the demonstration of causal relations between the various gene defects and the development of the disease, the establishment of phenotype/genotype relationships and finally the use of genetic data for diagnostic, prognostic and maybe therapeutic purposes.