title: A novel TBX20 loss‑of‑function mutation contributes to adult‑onset dilated cardiomyopathy or congenital atrial septal defect.
abstract: Dilated cardiomyopathy (DCM) is the most prevalent form of primary cardiomyopathy in humans and is a leading cause of heart failure and sudden cardiac death. Genetic abnormalities have been demonstrated to be a major contributor to the development of DCM. However, DCM is a genetically heterogeneous disease, and the genetic basis underlying DCM in a significant proportion of patients remains unclear. In the current study, the coding exons and splicing junction sites of the T‑Box 20 (TBX20) gene, which encodes a T‑box transcription factor essential for cardiac morphogenesis and structural remodeling, were sequenced in 115 unrelated patients with idiopathic DCM, and a novel heterozygous mutation, p.E143X, was identified in one patient. Genetic analysis of the mutation carrier's pedigree indicated that the nonsense mutation was present in all the living family members with DCM, and also in a female patient with a congenital atrial septal defect. The mutation, which was predicted to generate a truncated protein with only the N‑terminus and a fraction of the T‑box domain remaining, was absent in 800 control chromosomes. Functional assays using a dual‑luciferase reporter assay system revealed that the truncated TBX20 protein had no transcriptional activity in contrast to its wild‑type counterpart. Furthermore, the mutation abolished the synergistic activation between TBX20 and NK2 homeobox 5, or between TBX20 and GATA binding protein 4. The observations of the current study expand the mutation spectrum of TBX20 associated with DCM and congenital heart disease (CHD), which provide novel insight into the molecular mechanisms underlying DCM and CHD, suggesting the potential implications for the effective and personalized treatment of these diseases.
authors: Department of Emergency Medicine, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, P.R. China.
authors: Yi-Meng
authors: YM
authors: Zhou
authors: Department of Emergency Medicine, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, P.R. China.
authors: Xiao-Yong
authors: XY
authors: Dai
authors: Department of Cardiovascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P.R. China.
authors: Ri-Tai
authors: RT
authors: Huang
authors: Department of Cardiovascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P.R. China.
authors: Song
authors: S
authors: Xue
authors: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
authors: Ying-Jia
authors: YJ
authors: Xu
authors: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
authors: Xing-Biao
authors: XB
authors: Qiu
authors: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
authors: Yi-Qing
authors: YQ
authors: Yang
mesh_terms: D000328:Adult; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D050991:GATA4 Transcription Factor / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006344:Heart Septal Defects, Atrial / Q000235:genetics* / Q000378:metabolism; D006579:Heterozygote; D000072576:Homeobox Protein Nkx-2.5 / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D017354:Point Mutation; D020825:T-Box Domain Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human; D000072576:Homeobox Protein Nkx-2.5; C095552:NKX2-5 protein, human; D020825:T-Box Domain Proteins; C420984:TBX20 protein, human