Thierfelder L, Watkins H, MacRae C, Lamas R, McKenna W, Vosberg H P, Seidman J G, Seidman C E
Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115.
Cell. 1994 Jun 3;77(5):701-12. doi: 10.1016/0092-8674(94)90054-x.
We demonstrate that missense mutations (Asp175Asn; Glu180Gly) in the alpha-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 alpha-tropomyosin and cardiac troponin T as well as beta 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 stoichiometry of sarcomeric proteins can cause cardiac hypertrophy.
我们证明，α-原肌球蛋白基因中的错义突变（Asp175Asn；Glu180Gly）导致与15号染色体q2区域连锁的家族性肥厚型心肌病（FHC）。这些发现表明肌钙蛋白复合物的成分是其他FHC位点的候选基因，特别是心肌肌钙蛋白T，在本研究中它被定位到1号染色体。心肌肌钙蛋白T基因第15内含子剪接供体序列中的错义突变（Ile79Asn；Arg92Gln）和一个突变也被证明可导致FHC。由于α-原肌球蛋白、心肌肌钙蛋白T以及β肌球蛋白重链突变导致相同的表型，我们得出结论，FHC是一种肌节疾病。此外，由于剪接位点突变预计起无效等位基因的作用，我们认为肌节蛋白的异常化学计量可导致心肌肥厚。
