Frameshift variants in C10orf71 cause dilated cardiomyopathy in human, mouse, and organoid models

作者：Yang Li, Ke Ma, Zhujun Dong, Shijuan Gao, Jing Zhang, Shan Huang, Jie Yang, Guangming Fang, Yujie Li, Xiaowei Li, Carrie L. Welch, Emily Griffin, Prema Ramaswamy, Zaheer M. Valivullah, Xiuying Liu, Jianzeng Dong, Dao Wen Wang, Du, Wendy K. Chung, Yulin Li · 发表于：Journal of Clinical Investigation · 年份：2024 · DOI：10.1172/jci177172 · 被引用次数：15 · 研究领域：Cardiomyopathy and Myosin Studies、Congenital heart defects research、Muscle Physiology and Disorders

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.