α-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: A disease of the sarcomere
Thierfelder L., Watkins H., MacRae C., Lamas R., McKenna W., Vosberg HP., Seldman JG., Seidman CE.
We demonstrate that missense mutations (Asp175Asn; Glu180Gly) in the α-tropomyosin gene cause familial hypertrophic cardiomyopathy (FHC) linked to chromosome 15q2. These findings implicated components of the troponin complex as candidate genes at other FHC loci, particularly cardiac troponin T, which was mapped in this study to chromosome 1q. Missense mutations (Ile79Asn; Arg92Gln) and a mutation in the splice donor sequence of intron 15 of the cardiac troponin T gene are also shown to cause FHC. Because α-tropomyosin and cardiac troponin T as well as β myosin heavy chain mutations cause the same phenotype, we conclude that FHC is a disease of the sarcomere. Further, because the splice site mutation is predicted to function as a null allele, we suggest that abnormal stolchiometry of sarcomeric proteins can cause cardiac hypertrophy. © 1994.