2. Academic Validation
  3. Frameshift variants in C10orf71 cause dilated cardiomyopathy in human, mouse, and organoid models

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

  • J Clin Invest. 2024 Jun 17;134(12):e177172. doi: 10.1172/JCI177172.
Yang Li 1 2 3,  Ke Ma 1 2 3,  Zhujun Dong 1 2 3,  Shijuan Gao 1 2 3,  Jing Zhang 1 2 3,  Shan Huang 1 2 3,  Jie Yang 1 2 3,  Guangming Fang 1 2 3,  Yujie Li 4,  Xiaowei Li 5,  Carrie Welch 6,  Emily L Griffin 6,  Prema Ramaswamy 7,  Zaheer Valivullah 8,  Xiuying Liu 9,  Jianzeng Dong 1 5,  Dao Wen Wang 10,  Jie Du 1 2 3,  Wendy K Chung 11,  Yulin Li 1 2 3
Affiliations

Affiliations

  • 1 Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
  • 2 Beijing Institute of Heart, Lung & Blood Vessel Disease, Beijing, China.
  • 3 The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing, China.
  • 4 Novogene Co. Ltd., Beijing, China.
  • 5 Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  • 6 Department of Pediatrics, Columbia University, New York, New York, USA.
  • 7 Maimonides Medical Center, New York, New York, USA.
  • 8 Broad Institute, Cambridge, Massachusetts, USA.
  • 9 Changping Laboratory, Beijing, China.
  • 10 Division of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 11 Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
PMID: 38950288 DOI: 10.1172/JCI177172
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.

Keywords

Cardiology; Cardiovascular disease; Genetic diseases; Genetic variation; Genetics.

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