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Clinical Chemistry and Laboratory Medicine (CCLM)

Published in Association with the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM)

Editor-in-Chief: Plebani, Mario

Ed. by Gillery, Philippe / Greaves, Ronda / Lackner, Karl J. / Lippi, Giuseppe / Melichar, Bohuslav / Payne, Deborah A. / Schlattmann, Peter


IMPACT FACTOR 2017: 3.556

CiteScore 2017: 2.34

SCImago Journal Rank (SJR) 2017: 1.114
Source Normalized Impact per Paper (SNIP) 2017: 1.188

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1437-4331
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Volume 54, Issue 7

Issues

HAND1 loss-of-function mutation associated with familial dilated cardiomyopathy

Yi-Meng Zhou
  • Corresponding author
  • Department of Emergency Medicine, Yangpu Hospital, Tongji University School of Medicine, Shanghai, P.R. China
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/ Xiao-Yong Dai
  • Department of Emergency Medicine, Yangpu Hospital, Tongji University School of Medicine, Shanghai, P.R. China
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/ Xing-Biao Qiu
  • Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, P.R. China
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/ Fang Yuan
  • Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, P.R. China
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/ Ruo-Gu Li
  • Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, P.R. China
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/ Ying-Jia Xu
  • Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, P.R. China
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/ Xin-Kai Qu
  • Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, P.R. China
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/ Ri-Tai Huang
  • Department of Cardiovascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
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/ Song Xue
  • Department of Cardiovascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
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/ Yi-Qing Yang
  • Corresponding author
  • Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, P.R. China
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Published Online: 2015-11-18 | DOI: https://doi.org/10.1515/cclm-2015-0766

Abstract

Background: The basic helix-loop-helix transcription factor HAND1 is essential for cardiac development and structural remodeling, and mutations in HAND1 have been causally linked to various congenital heart diseases. However, whether genetically compromised HAND1 predisposes to dilated cardiomyopathy (DCM) in humans remains unknown.

Methods: The whole coding region and splicing junctions of the HAND1 gene were sequenced in 140 unrelated patients with idiopathic DCM. The available family members of the index patient carrying an identified mutation and 260 unrelated ethnically matched healthy individuals used as controls were genotyped for HAND1. The functional effect of the mutant HAND1 was characterized in contrast to its wild-type counterpart by using a dual-luciferase reporter assay system.

Results: A novel heterozygous HAND1 mutation, p.R105X, was identified in a family with DCM transmitted as an autosomal dominant trait, which co-segregated with DCM in the family with complete penetrance. The nonsense mutation was absent in 520 control chromosomes. Functional analyses unveiled that the mutant HAND1 had no transcriptional activity. Furthermore, the mutation abolished the synergistic activation between HAND1 and GATA4, another crucial cardiac transcription factors that has been associated with various congenital cardiovascular malformations and DCM.

Conclusions: This study firstly reports the association of HAND1 loss-of-function mutation with increased susceptibility to DCM in humans, which provides novel insight into the molecular mechanisms underpinning DCM.

Keywords: dilated cardiomyopathy; genetics; HAND1; reporter gene; transcription factor

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About the article

Corresponding authors: Dr. Yi-Meng Zhou, Department of Emergency Medicine, Yangpu Hospital, Tongji University School of Medicine, 450 Tengyue Road, Shanghai 200090, P.R. China, Phone: +86 21 65690520, Fax: +86 21 65696249, E-mail: ; and Dr. Yi-Qing Yang, Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai 200030, P.R. China, Phone: +86 21 62821990, Fax: +86 21 62821105, E-mail:

aYi-Meng Zhou and Xiao-Yong Dai contributed equally to this work.


Received: 2015-08-09

Accepted: 2015-10-13

Published Online: 2015-11-18

Published in Print: 2016-07-01


Citation Information: Clinical Chemistry and Laboratory Medicine (CCLM), Volume 54, Issue 7, Pages 1161–1167, ISSN (Online) 1437-4331, ISSN (Print) 1434-6621, DOI: https://doi.org/10.1515/cclm-2015-0766.

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