title: A Novel TBX1 Loss-of-Function Mutation Associated with Congenital Heart Disease.
abstract: Congenital heart disease (CHD) is the most prevalent type of birth defect in humans and is the leading non-infectious cause of infant death worldwide. There is a growing body of evidence demonstrating that genetic defects play an important role in the pathogenesis of CHD. However, CHD is a genetically heterogeneous disease and the genetic basis underpinning CHD in an overwhelming majority of patients remains unclear. In this study, the coding exons and splice junction sites of the TBX1 gene, which encodes a T-box homeodomain transcription factor essential for proper cardiovascular morphogenesis, were sequenced in 230 unrelated children with CHD. The available family members of the index patient carrying an identified mutation and 200 unrelated ethnically matched healthy individuals used as controls were subsequently genotyped for TBX1. The functional effect of the TBX1 mutation was predicted by online program MutationTaster and characterized by using a dual-luciferase reporter assay system. As a result, a novel heterozygous TBX1 mutation, p.Q277X, was identified in an index patient with double outlet right ventricle (DORV) and ventricular septal defect (VSD). Genetic analysis of the proband's available relatives showed that the mutation co-segregated with CHD transmitted in an autosomal dominant pattern with complete penetrance. The nonsense mutation, which was absent in 400 control chromosomes, altered the amino acid that was completely conserved evolutionarily across species and was predicted to be disease-causing by MutationTaster. Biochemical analysis revealed that Q277X-mutant TBX1 lost transcriptional activating function when compared with its wild-type counterpart. This study firstly associates TBX1 loss-of-function mutation with enhanced susceptibility to DORV and VSD in humans, which provides novel insight into the molecular mechanism underlying CHD and suggests potential implications for the development of new preventive and therapeutic strategies for CHD.
authors: Department of Pediatrics, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China.
authors: Yun
authors: Y
authors: Pan
authors: Department of Pediatrics, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China.
authors: Zha-Gen
authors: ZG
authors: Wang
authors: Department of Pediatrics, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China. xingyuanliu69@163.com.
authors: Xing-Yuan
authors: XY
authors: Liu
authors: Department of Pediatrics, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China.
authors: Hong
authors: H
authors: Zhao
authors: Department of Pediatrics, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China.
authors: Ning
authors: N
authors: Zhou
authors: Department of Pediatrics, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China.
authors: Gui-Fen
authors: GF
authors: Zheng
authors: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China.
authors: Xing-Biao
authors: XB
authors: Qiu
authors: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China.
authors: Ruo-Gu
authors: RG
authors: Li
authors: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China.
authors: Fang
authors: F
authors: Yuan
authors: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China.
authors: Hong-Yu
authors: HY
authors: Shi
authors: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China.
authors: Xu-Min
authors: XM
authors: Hou
authors: Department of Cardiology, Cardiovascular Research Laboratory, and Central Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai, 200030, China. dryyq@tongji.edu.cn.
authors: Yi-Qing
authors: YQ
authors: Yang
mesh_terms: D002675:Child, Preschool; D005091:Exons; D005260:Female; D020022:Genetic Predisposition to Disease; D006330:Heart Defects, Congenital / Q000145:classification* / Q000235:genetics*; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D020825:T-Box Domain Proteins / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D018398:Homeodomain Proteins; D020825:T-Box Domain Proteins; C108625:TBX1 protein, human; D014157:Transcription Factors
keywords: Congenital heart disease; Genetics; Reporter gene; TBX1; Transcription factor