Frameshift variants in C10orf71 cause dilated cardiomyopathy in human, mouse, and organoid models
Yang Li, … , Wendy K. Chung, Yulin Li
Yang Li, … , Wendy K. Chung, Yulin Li
Published June 17, 2024
Citation Information: J Clin Invest. 2024;134(12):e177172. https://doi.org/10.1172/JCI177172.
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Research Article Cardiology Genetics

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

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.

Authors

Yang Li, Ke Ma, Zhujun Dong, Shijuan Gao, Jing Zhang, Shan Huang, Jie Yang, Guangming Fang, Yujie Li, Xiaowei Li, Carrie Welch, Emily L. Griffin, Prema Ramaswamy, Zaheer Valivullah, Xiuying Liu, Jianzeng Dong, Dao Wen Wang, Jie Du, Wendy K. Chung, Yulin Li

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Figure 6

C10orf71-defective CMs exhibit impaired contractile function.

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C10orf71-defective CMs exhibit impaired contractile function. (A) Repre...
(A) Representative images for cells used in IonOptix measurements. (B) Quantification of CM width shown in panel A (n = 48–50). ***P < 0.001 in t test. (C) Representative traces of sarcomere shortening in paced ventricular myocytes isolated from WT and KO mice. (D) Sarcomere shortening (expressed as the percentage of resting sarcomere length, SL), departure velocity, and return velocity in WT and KO CMs. *P < 0.05, **P < 0.01 in t test. (E) Relative mRNA levels of C10orf71 during WT1 hiPSC-CMs differentiation (n = 3 independent differentiations). (F) Representative images showing immunofluorescence staining of pluripotent markers (OCT4 and SOX2) in WT1 and Mut1 iPSCs. DAPI, nuclei stain, blue. Scale bar: 100 μm. (G) Representative images for WT1 and Mut1 monolayer hiPSC-CMs sheets. (H) Relative mRNA levels of TTN, TNNT2, MYH7, and ACTN2 during WT1 and Mut1 hiPSC-CMs differentiation (n = 3 independent differentiations). *P < 0.05, **P < 0.01, ***P < 0.001 in 2-way ANOVA followed by Šidák’s post hoc test. (I) MEA parameters for WT1 and Mut1 hiPSC-CMs differentiated for 40 days, including beat amplitude, beat period, and excitation-contraction delay (n = 18 for WT1 and n = 26 for Mut1). **P < 0.01, t test. *P < 0.05 in Mann-Whitney test. (J) Morphological changes of iPSC-HO at differentiation stages. Scale bar: 1 mm. (K) Contractility based on dynamic morphological information (n = 9 for WT1 and n = 12 for Mut1). ***P < 0.001 in t test. (L) FP waveforms of WT1 and Mut1 iPSC-HO. (M) MEA parameters for WT1 and Mut1 iPSC-HO, including beat amplitude, beat period, and excitation-contraction delay (n = 8 for WT1 and n = 7 for Mut1). *P < 0.05, t test. Each dot represents 1 biological repeat. Data represent mean ± SD.