title: A HAND2 Loss-of-Function Mutation Causes Familial Ventricular Septal Defect and Pulmonary Stenosis.
abstract: Congenital heart disease (CHD) is the most common developmental abnormality, and is the leading noninfectious cause of mortality in neonates. Increasing evidence demonstrates that genetic defects play an important role in the pathogenesis of CHD. However, CHD exhibits substantial heterogeneity, and the genetic determinants for CHD remain unknown in the overwhelming majority of cases. In the current study, the coding exons and flanking introns of the HAND2 gene, which encodes a basic helix-loop-helix transcription factor essential for normal cardiovascular development, were sequenced in 192 unrelated patients with CHD, and a novel heterozygous mutation, p.S65I, was identified in a patient with congenital ventricular septal defect (VSD). Genetic analysis of the index patient's pedigree revealed that the mutation was present in all seven affected family members available, but absent in the 13 unaffected family members examined. Besides, in addition to VSD, five of the proband's close relatives also had pulmonary stenosis (PS), and the proband's son also had double outlet right ventricle (DORV). The missense mutation, which altered an evolutionarily conserved amino acid, was absent in 300 unrelated, ethnically matched healthy individuals. Biological analyses using a dual-luciferase reporter assay system showed that the mutant HAND2 was associated with significantly diminished transcriptional activity. Furthermore, the mutation abolished the synergistic activation between HAND2 and GATA4, as well as NKX2.5-two other cardiac core transcriptional factors that have been causally linked to CHD. These findings indicate that HAND2 loss-of-function mutation contributes to human CHD, perhaps via its interaction with GATA4 and NKX2.5.
authors: Department of Cardiology, Jing'an District Central Hospital, 200040 Shanghai, China.
authors: Yu-Min
authors: YM
authors: Sun
authors: Department of Cardiology, Jing'an District Central Hospital, 200040 Shanghai, China wang_jun98@sina.cn dryyq@tongji.edu.cn.
authors: Jun
authors: J
authors: Wang
authors: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, 200030, China.
authors: Xing-Biao
authors: XB
authors: Qiu
authors: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, 200030, China.
authors: Fang
authors: F
authors: Yuan
authors: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, 200030, China.
authors: Ruo-Gu
authors: RG
authors: Li
authors: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, 200030, China.
authors: Ying-Jia
authors: YJ
authors: Xu
authors: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, 200030, China.
authors: Xin-Kai
authors: XK
authors: Qu
authors: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, 200030, China.
authors: Hong-Yu
authors: HY
authors: Shi
authors: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, 200030, China.
authors: Xu-Min
authors: XM
authors: Hou
authors: Department of Cardiovascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 200127, China.
authors: Ri-Tai
authors: RT
authors: Huang
authors: Department of Cardiovascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 200127, China.
authors: Song
authors: S
authors: Xue
authors: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, 200030, China wang_jun98@sina.cn dryyq@tongji.edu.cn.
authors: Yi-Qing
authors: YQ
authors: Yang
mesh_terms: D000293:Adolescent; D000483:Alleles; D019943:Amino Acid Substitution; D009320:Atrial Natriuretic Factor / Q000235:genetics; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D003062:Codon; D004252:DNA Mutational Analysis; D005260:Female; D050991:GATA4 Transcription Factor / Q000235:genetics / Q000378:metabolism; D056726:Genetic Association Studies; D006345:Heart Septal Defects, Ventricular / Q000175:diagnosis / Q000235:genetics*; D000072576:Homeobox Protein Nkx-2.5 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D010375:Pedigree; D011401:Promoter Regions, Genetic; D011666:Pulmonary Valve Stenosis / Q000175:diagnosis / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D015533:Transcriptional Activation; D055815:Young Adult
chemical_list: D009320:Atrial Natriuretic Factor; D051792:Basic Helix-Loop-Helix Proteins; D003062:Codon; D050991:GATA4 Transcription Factor; D000072576:Homeobox Protein Nkx-2.5; D014157:Transcription Factors; C498765:HAND2 protein, human
keywords: HAND2; congenital heart disease; genetics; reporter gene assay; transcription factor