PDF(Pubmed)
Abstract：
Research advances over the past 30 years have confirmed a critical role for genetics in the etiology of dilated cardiomyopathies (DCMs). However, full knowledge of the genetic architecture of DCM remains incomplete. We identified candidate DCM causal gene, C10orf71, in a large family with 8 patients with DCM by whole-exome sequencing. Four loss-of-function variants of C10orf71 were subsequently identified in an additional group of492 patients with sporadic DCM from 2 independent cohorts. C10orf71 was found to be an intrinsically disordered protein specifically expressed in cardiomyocytes. C10orf71-KO mice had abnormal heart morphogenesis during embryonic development and cardiac dysfunction as adults with altered expression and splicing of contractile cardiac genes. C10orf71-null cardiomyocytes exhibited impaired contractile function with unaffected sarcomere structure. Cardiomyocytes and heart organoids derived from human induced pluripotent stem cells with C10orf71 frameshift variants also had contractile defects with normal electrophysiological activity. A rescue study using a cardiac myosin activator, omecamtiv mecarbil, restored contractile function in C10orf71-KO mice. These data support C10orf71 as a causal gene for DCM by contributing to the contractile function of cardiomyocytes. Mutation-specific pathophysiology may suggest therapeutic targets and more individualized therapy.
摘要：
过去30年的研究进展证实了遗传学在扩张型心肌病（DCMs）的病因学中的关键作用。然而,对DCM遗传结构的全面了解仍然不完整。我们确定了候选DCM致病基因，C10orf71，在一个有8名DCM患者的大家庭中，通过全外显子组测序。随后在来自2个独立队列的另外492例散发性DCM患者中发现了C10orf71的4种功能丧失变体。发现C10orf71是在心肌细胞中特异性表达的内在无序蛋白。C10orf71-KO小鼠在胚胎发育和心脏功能障碍期间具有异常的心脏形态发生，成年后收缩心脏基因的表达和剪接发生改变。C10orf71空心肌细胞表现出收缩功能受损，肌节结构未受影响。来自具有C10orf71移码变体的人诱导多能干细胞的心肌细胞和心脏类器官也具有具有正常电生理活性的收缩缺陷。一项使用心脏肌球蛋白激活剂的救援研究，omecamtivmecarbil,恢复C10orf71-KO小鼠的收缩功能。这些数据通过促进心肌细胞的收缩功能而支持C10orf71作为DCM的致病基因。突变特异性病理生理学可能提示治疗靶标和更个性化的治疗。
