title: HAND1 Loss-of-Function Mutation Causes Tetralogy of Fallot.
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.
authors.affiliation: Department of Cardiovascular Medicine, East Hospital, Tongji University School of Medicine, Shanghai, 200120, China. wang_juan1989@sina.cn.
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Cardiovascular Medicine, East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
authors.forename: Xiao-Qing
authors.initials: XQ
authors.lastname: Hu
authors.affiliation: Department of Cardiology, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China.
authors.forename: Yu-Han
authors.initials: YH
authors.lastname: Guo
authors.affiliation: Department of Cardiology, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China.
authors.forename: Jian-Yun
authors.initials: JY
authors.lastname: Gu
authors.affiliation: Department of Cardiology, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China.
authors.forename: Jia-Hong
authors.initials: JH
authors.lastname: Xu
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China.
authors.forename: Yan-Jie
authors.initials: YJ
authors.lastname: Li
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China.
authors.forename: Xiao-Xiao
authors.initials: XX
authors.lastname: Yang
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China. dryyq@tongji.edu.cn.|Department of Cardiovascular Research Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China. dryyq@tongji.edu.cn.|Department of Central Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China. dryyq@tongji.edu.cn.
authors.forename: Yi-Qing
authors.initials: YQ
authors.lastname: Yang
mesh_terms: D000595:Amino Acid Sequence; D044466:Asian People / Q000235:genetics*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D002675:Child, Preschool; D002681:China; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D006579:Heterozygote; D006801:Humans; D007223:Infant; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D013771:Tetralogy of Fallot / Q000235:genetics*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; C097341:helix-loop-helix protein, eHAND
keywords: Congenital heart disease; Genetics; HAND1; Reporter gene assay; Tetralogy of Fallot; Transcription factor