Novel cardiac troponin T mutation as a cause of familial dilated cardiomyopathy

Background-Familial dilated cardiomyopathy (FDCM) and hypertrophic cardiomy opathy (FHCM) are the 2 most common forms of primary cardiac muscle disease s. Studies indicate that mutations in sarcomeric proteins are responsible f or FHCM and suggest that mutations in cytoskeletal proteins cause FDCM. Evi dence is evolving, however, that such conclusions are premature. Methods and Results-A novel missense mutation in the cardiac troponin T gen e was identified by direct sequencing and confirmed by endonuclease restric tion analysis in a large family with FDCM that we had previously mapped to chromosome 1q32. The mutation substitutes tryptophan for a highly conserved amino acid, arginine, at amino acid residue 141 (Arg141Trp). The mutation occurs within the tropomyosin-binding domain of cardiac troponin T and alte rs the charge of the residue. This mutation cosegregates with the disease, being present in all 14 living affected individuals. The mutation was not f ound in 100 normal control subjects. Clinical features were congestive hear t failure with premature deaths. The age of onset and severity of the disea se are highly variable, with incomplete penetrance. Because 15 mutations in troponin T are known to cause FHCM, 219 probands with FHCM were screened, and none had the mutation. Conclusions-Thus, the novel cardiac troponin T mutation Arg141Trp is respon sible for FDCM in our family. Because several mutations in troponin T have already been recognized to be responsible for FHCM, it appears that the phe notype, whether it be hypertrophy or dilatation, is determined by the speci fic mutation rather than the gene.