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

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

Authors :
Zhou YM
Dai XY
Qiu XB
Yuan F
Li RG
Xu YJ
Qu XK
Huang RT
Xue S
Yang YQ
Source :
Clinical chemistry and laboratory medicine [Clin Chem Lab Med] 2016 Jul 01; Vol. 54 (7), pp. 1161-7.
Publication Year :
2016

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.<br />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.<br />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.<br />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.

Details

Language :
English
ISSN :
1437-4331
Volume :
54
Issue :
7
Database :
MEDLINE
Journal :
Clinical chemistry and laboratory medicine
Publication Type :
Academic Journal
Accession number :
26581070
Full Text :
https://doi.org/10.1515/cclm-2015-0766