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Pediatric Cardiology
Published in: Pediatric Cardiology 3/2017

01-03-2017 | Original Article

HAND1 Loss-of-Function Mutation Causes Tetralogy of Fallot

Authors: Juan Wang, Xiao-Qing Hu, Yu-Han Guo, Jian-Yun Gu, Jia-Hong Xu, Yan-Jie Li, Ning Li, Xiao-Xiao Yang, Yi-Qing Yang

Published in: Pediatric Cardiology | Issue 3/2017

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Abstract

As the most prevalent form of birth defect in humans worldwide, congenital heart disease (CHD) is responsible for substantial morbidity and is still the leading cause of birth defect-related demises. Increasing evidence demonstrates that genetic defects play an important role in the pathogenesis of CHD, and mutations in multiple genes, especially in those coding for cardiac core transcription factors, have been causally linked to various CHDs. Nevertheless, CHD is a genetically heterogeneous disease and the genetic determinants underpinning CHD in an overwhelming majority of patients remain elusive. In the current study, genomic DNA was extracted from venous blood samples of 165 unrelated patients with CHD, and the coding exons and splicing junction sites of the HAND1 gene, which encodes a basic helix-loop-helix transcription factor essential for cardiovascular development, were sequenced. As a result, a novel heterozygous mutation, p.R118C, was identified in a patient with tetralogy of Fallot (TOF). The missense mutation, which was absent in 600 referential chromosomes, altered the amino acid that was completely conserved evolutionarily. Biological assays with a dual-luciferase reporter assay system revealed that the R118C-mutant HAND1 protein had significantly reduced transcriptional activity when compared with its wild-type counterpart. Furthermore, the mutation significantly decreased the synergistic activation of a downstream target gene between HAND1 and GATA4, another cardiac core transcription factor associated with TOF. To our knowledge, this is the first report on the association of a HAND1 loss-of-function mutation with enhanced susceptibility to TOF in humans. The findings provide novel insight into the molecular etiology underlying TOF, suggesting potential implications for the improved prophylactic and therapeutic strategies for TOF.
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Metadata
Title
HAND1 Loss-of-Function Mutation Causes Tetralogy of Fallot
Authors
Juan Wang
Xiao-Qing Hu
Yu-Han Guo
Jian-Yun Gu
Jia-Hong Xu
Yan-Jie Li
Ning Li
Xiao-Xiao Yang
Yi-Qing Yang
Publication date
01-03-2017
Publisher
Springer US
Published in
Pediatric Cardiology / Issue 3/2017
Print ISSN: 0172-0643
Electronic ISSN: 1432-1971
DOI
https://doi.org/10.1007/s00246-016-1547-8

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