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Identification and Functional Characterization of an ISL1 Mutation Predisposing to Dilated Cardiomyopathy

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Abstract

Dilated cardiomyopathy (DCM) is the most prevalent cause of non-ischemic cardiac failure and the commonest indication for cardiac transplantation. Compelling evidence highlights the pivotal roles of genetic defects in the occurrence of DCM. Nevertheless, the genetic determinants underpinning DCM remain largely obscure. In this study, the coding regions of ISL1, which encodes a transcription factor critical for embryonic cardiogenesis and postnatal cardiac remodeling, were sequenced in 216 unrelated patients with DCM, and a novel heterozygous ISL1 mutation, NM_002202.2: c.631A>T; p.(Lys211*), was identified in a proband. The mutation, which co-segregated with DCM in the family, was absent in 238 unrelated controls, as well as in the Genome Aggregation and the Exome Aggregation Consortium population databases. Functional analyses unveiled that the mutant ISL1 protein lost transcriptional activity alone or in synergy with TBX20 or GATA4, two other transcription factors associated with DCM. These findings indicate ISL1 as a new gene of DCM.

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Abbreviations

DCM:

Dilated cardiomyopathy

CHD:

Congenital heart disease

VSD:

Ventricular septal defect

PCR:

Polymerase chain reaction

SD:

Standard deviation

HD:

Homeodomain

TAD:

Transcriptional activation domain

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Acknowledgments

The authors acknowledge the study subjects for their participation in the study.

Funding

This work was financially supported by the grants from the National Natural Science Foundation of China (No. 81470372), the Natural Science Foundation of Minhang District, Shanghai, China (No. 2018MHZ072), the Program of the Health and Family Planning Commission of Shanghai, China (No. M20170348), and the Key Project of the Fifth People’s Hospital of Shanghai, Fudan University, China (No. 2018WYZD05).

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  1. Ying-Jia Xu and Zhang-Sheng Wang contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiology, Cardiovascular Research Laboratory, and Center for Complex Arrhythmias of Minhang District, The Fifth People’s Hospital of Shanghai, Fudan University, No. 801 Heqing Road, Shanghai, 200240, China

    Ying-Jia Xu, Zhang-Sheng Wang, Chen-Xi Yang, Ruo-Min Di, Qi Qiao, Xiu-Mei Li, Jia-Ning Gu, Xiao-Juan Guo & Yi-Qing Yang

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  1. Ying-Jia Xu
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Correspondence to Yi-Qing Yang.

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The study was carried out in conformity with the ethical standards established in the 1964 Declaration of Helsinki and its later amendments and was approved by the Medical Ethics Committee of the Fifth People′s Hospital of Shanghai, Fudan University, China. All study participants provided their informed consent prior to the study.

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The authors declare that they have no conflict of interest.

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All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. No animal studies were carried out by the authors for this article.

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Xu, YJ., Wang, ZS., Yang, CX. et al. Identification and Functional Characterization of an ISL1 Mutation Predisposing to Dilated Cardiomyopathy. J. of Cardiovasc. Trans. Res. 12, 257–267 (2019). https://doi.org/10.1007/s12265-018-9851-8

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