Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
J Am Coll Cardiol. 2010 Jan 26;55(4):320-9. doi: 10.1016/j.jacc.2009.11.017.
We sought to further define the role of sarcomere mutations in dilated cardiomyopathy (DCM) and associated clinical phenotypes.
Mutations in several contractile proteins contribute to DCM, but definitive evidence for the roles of most sarcomere genes remains limited by the lack of robust genetic support.
Direct sequencing of 6 sarcomere genes was performed on 334 probands with DCM. A novel D230N missense mutation in the gene encoding alpha-tropomyosin (TPM1) was identified. Functional assessment was performed by the use of an in vitro reconstituted sarcomere complex to evaluate ATPase regulation and Ca(2+) affinity as correlates of contractility.
TPM1 D230N segregated with DCM in 2 large unrelated families. This mutation altered an evolutionarily conserved residue and was absent in >1,000 control chromosomes. In vitro studies demonstrated major inhibitory effects on sarcomere function with reduced Ca(2+) sensitivity, maximum activation, and Ca(2+) affinity compared with wild-type TPM1. Clinical manifestations ranged from decompensated heart failure or sudden death in those presenting early in life to asymptomatic left ventricular dysfunction in those diagnosed during adulthood. Notably, several affected infants had remarkable improvement.
Genetic segregation in 2 unrelated families and functional analyses conclusively establish a pathogenic role for TPM1 mutations in DCM. In vitro results demonstrate contrasting effects of DCM and hypertrophic cardiomyopathy mutations in TPM1, suggesting that specific functional consequences shape cardiac remodeling. Along with previous reports, our data support a distinctive, age-dependent phenotype with sarcomere-associated DCM where presentation early in life is associated with severe, sometimes lethal, disease. These observations have implications for the management of familial DCM.
我们旨在进一步明确肌节突变在扩张型心肌病（DCM）和相关临床表型中的作用。
几种收缩蛋白的突变导致 DCM，但由于缺乏强有力的遗传支持，大多数肌节基因的确切作用仍存在局限性。
对 334 名 DCM 先证者进行了 6 个肌节基因的直接测序。鉴定到编码α-原肌球蛋白（TPM1）的基因中的一个新的 D230N 错义突变。通过使用体外重组成肌节复合物来评估 ATP 酶调节和 Ca2+亲和力，作为收缩性的相关指标，进行功能评估。
TPM1 D230N 在 2 个大型非相关家族中与 DCM 共分离。该突变改变了一个进化上保守的残基，并且在 >1000 个对照染色体中不存在。体外研究表明，与野生型 TPM1 相比，该突变对肌节功能具有主要的抑制作用，Ca2+敏感性、最大激活和 Ca2+亲和力降低。临床表现从生命早期出现失代偿性心力衰竭或猝死到成年期诊断出无症状左心室功能障碍不等。值得注意的是，一些受影响的婴儿有明显的改善。
在 2 个不相关的家族中进行的遗传分离和功能分析，明确确立了 TPM1 突变在 DCM 中的致病性作用。体外结果表明，TPM1 中的 DCM 和肥厚型心肌病突变具有相反的作用，表明特定的功能后果塑造了心脏重塑。与之前的报道一致，我们的数据支持一种独特的、与年龄相关的表型，具有与肌节相关的 DCM，其早期发病与严重、有时致命的疾病相关。这些观察结果对家族性 DCM 的管理具有重要意义。
