Mutations in CHMP4C Cause Dilated Cardiomyopathy <i>via</i> Dysregulation of Autophagy

Abstract

Background: Gene mutations have been implicated in DCM. However, due to the difficulty of clinical genetic diagnosis, additional causal genes potentially related to DCM remain to be discovered. Methods: We screened for gene mutations in more than 400 cases from families with hereditary cardiovascular disease using whole-exome sequencing and then validated the biological functions of CHMP4C mutations in zebrafish models. To further assess the mechanism of CHMP4C mutations, we determined the potential signaling pathway in a cell line. Results: We identified via whole-exome sequencing CHMP4C variants that segregated with DCM in four families among a total of 411 families. We further validated the function of CHMP4C in heart function in zebrafish models and found that overexpression of CHMP4C variants resulted in cardiac malformation, pericardial edema and an increased heart rate, consistent with CHMP4C mutation-associated findings in DCM patients. Furthermore, mutations in CHMP4C impaired autophagy and activated apoptosis in HEK293T cells, suggesting that the molecular mechanism of CHMP4C is involved in heart development. Conclusions: CHMP4C is a novel candidate gene causing DCM and may play a critical role in cardiac development by regulating autophagy. Funding Statement: This work was supported by NSFC Grants (# 81671685, #31625013, and #91732302); Shanghai Science and Technology Committee Foundation (#17411954400); Shanghai Brain-Intelligence Project from STCSM (16JC1420501); Strategic Priority Research Program of the Chinese Academy of Sciences (XDBS01060200); Program of Shanghai Academic Research Leader, the Open Large Infrastructure Research of Chinese Academy of Sciences; and the Shanghai Municipal Science and Technology Major Project (#2018SHZDZX05). Declaration of Interests: None. Ethics Approval Statement: The study was approved by the Ethics Committee of Zhongshan Hospital, Fudan University (No. B2016-016(2)R).