Detection and functional characterization of a novel MEF2A variation responsible for familial dilated cardiomyopathy
Author:
Qiao Qi1, Zhao Cui-Mei2, Yang Chen-Xi1, Gu Jia-Ning1, Guo Yu-Han1, Zhang Min3, Li Ruo-Gu3, Qiu Xing-Biao3, Xu Ying-Jia1, Yang Yi-Qing145
Affiliation:
1. Department of Cardiology , Shanghai Fifth People′s Hospital, Fudan University , Shanghai , P.R. China 2. Department of Cardiology , Tongji Hospital, Tongji University School of Medicine , Shanghai , P.R. China 3. Department of Cardiology , Shanghai Chest Hospital, Shanghai Jiao Tong University , Shanghai , P.R. China 4. Cardiovascular Research Laboratory, Shanghai Fifth People′s Hospital, Fudan University , Shanghai , P.R. China 5. Center Laboratory, Shanghai Fifth People′s Hospital, Fudan University , Shanghai , P.R. China
Abstract
Abstract
Objectives
Dilated cardiomyopathy (DCM) represents the most frequent form of cardiomyopathy, leading to heart failure, cardiac arrhythmias and death. Accumulating evidence convincingly demonstrates the crucial role of genetic defects in the pathogenesis of DCM, and over 100 culprit genes have been implicated with DCM. However, DCM is of substantial genetic heterogeneity, and the genetic determinants underpinning DCM remain largely elusive.
Methods
Whole-exome sequencing and bioinformatical analyses were implemented in a consanguineous Chinese family with DCM. A total of 380 clinically annotated control individuals and 166 more DCM index cases then underwent Sanger sequencing analysis for the identified genetic variation. The functional characteristics of the variant were delineated by utilizing a dual-luciferase assay system.
Results
A heterozygous variation in the MEF2A gene (encoding myocyte enhancer factor 2A, a transcription factor pivotal for embryonic cardiogenesis and postnatal cardiac adaptation), NM_001365204.1: c.718G>T; p. (Gly240*), was identified, and verified by Sanger sequencing to segregate with autosome-dominant DCM in the family with complete penetrance. The nonsense variation was neither detected in 760 control chromosomes nor found in 166 more DCM probands. Functional analyses revealed that the variant lost transactivation on the validated target genes MYH6 and FHL2, both causally linked to DCM. Furthermore, the variation nullified the synergistic activation between MEF2A and GATA4, another key transcription factor involved in DCM.
Conclusions
The findings firstly indicate that MEF2A loss-of-function variation predisposes to DCM in humans, providing novel insight into the molecular mechanisms of DCM and suggesting potential implications for genetic testing and prognostic evaluation of DCM patients.
Funder
Basic Research Project of Shanghai, China Science and Technology Support Project of Medical Guidance, Shanghai, China Clinical Research Project of Tongji Hospital, Tongji University, Shanghai, China Experimental Animal Project of Shanghai, China Program of Outstanding Young Scientists of Tongji Hospital, Tongji University, Shanghai, China Clinical Medicine Program of Shanghai, China
Publisher
Walter de Gruyter GmbH
Subject
Biochemistry, medical,Clinical Biochemistry,General Medicine
Reference50 articles.
1. Marrow, BA, Cook, SA, Prasad, SK, McCann, GP. Emerging techniques for risk stratification in nonischemic dilated cardiomyopathy: JACC review topic of the week. J Am Coll Cardiol 2020;75:1196–207. https://doi.org/10.1016/j.jacc.2019.12.058. 2. Merlo, M, Cannatà, A, Gobbo, M, Stolfo, D, Elliott, PM, Sinagra, G. Evolving concepts in dilated cardiomyopathy. Eur J Heart Fail 2018;20:228–39. https://doi.org/10.1002/ejhf.1103. 3. Cannatà, A, De Angelis, G, Boscutti, A, Normand, C, Artico, J, Gentile, P, et al.. Arrhythmic risk stratification in non-ischaemic dilated cardiomyopathy beyond ejection fraction. Heart 2020;106:656–64. https://doi.org/10.1136/heartjnl-2019-315942. 4. Stolfo, D, Albani, S, Savarese, G, Barbati, G, Ramani, F, Gigli, M, et al.. Risk of sudden cardiac death in New York Heart Association class I patients with dilated cardiomyopathy: a competing risk analysis. Int J Cardiol 2020;307:75–81. https://doi.org/10.1016/j.ijcard.2020.02.025. 5. Tabish, AM, Azzimato, V, Alexiadis, A, Buyandelger, B, Knöll, R. Genetic epidemiology of titin-truncating variants in the etiology of dilated cardiomyopathy. Biophys Rev 2017;9:207–23. https://doi.org/10.1007/s12551-017-0265-7.
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