ALPHA-TROPOMYOSIN AND CARDIAC TROPONIN-T MUTATIONS CAUSE FAMILIAL HYPERTROPHIC CARDIOMYOPATHY - A DISEASE OF THE SARCOMERE

We demonstrate that missense mutations (Asp175Asn; Glu180Gly) in the a lpha-tropomyosin gene cause familial hypertrophic cardiomyopathy (FHC) linked to chromosome 15q2. These findings implicated components of th e troponin complex as candidate genes at other FHC loci, particularly cardiac troponin T, which was mapped in this study to chromosome 1q. M issense mutations (Ile79Asn; Arg92Gln) and a mutation in the splice do nor sequence of intron 15 of the cardiac troponin T gene are also show n to cause FHC. Because alpha-tropomyosin and cardiac troponin T as we ll as beta myosin heavy chain mutations cause the same phenotype, we c onclude that FHC is a disease of the sarcomere. Further, because the s plice site mutation is predicted to function as a null allele, we sugg est that abnormal stoichiometry of sarcomeric proteins can cause cardi ac hypertrophy.