title: A novel TBX5 loss-of-function mutation associated with sporadic dilated cardiomyopathy.
abstract: Dilated cardiomyopathy (DCM) represents the most prevalent form of primary cardiomyopathy, and is the most common reason for heart transplantation and a major cause of congestive heart failure. Aggregating evidence demonstrates that genetic defects are associated with DCM, and a great number of mutations in >50 genes have been linked to DCM. However, DCM is a genetically heterogeneous disorder and the genetic components underpinning DCM in a significant proportion of patients remain unknown. In the present study, the coding exons and flanking exon‑intron boundaries of the T-Box 5 (TBX5) gene, which encodes a T‑box transcription factor required for normal cardiac development, were sequenced in 146 unrelated patients with sporadic DCM. The functional characteristics of the mutant TBX5 were assayed in contrast to its wild‑type counterpart by using a dual‑luciferase reporter assay system. As a result, a novel heterozygous TBX5 mutation, p.A143T, was identified in a patient with sporadic DCM. The missense mutation, which was absent in 400 control chromosomes, altered the amino acid that was completely conserved evolutionarily among species. Biological analyses revealed that the A143T mutation of TBX5 was associated with significantly decreased transcriptional activity on the promoter of the target gene atrial natriuretic factor (ANF), when compared to its wild‑type counterpart. Furthermore, the A143T mutation abolished the synergistic activation of the ANF promoter between TBX5 and GATA binding protein 4 (GATA4), another crucial transcriptional factor for heart development. To the best of our knowledge, this is the first report on the association of a TBX5 loss‑of‑function mutation with an enhanced susceptibility to sporadic DCM, providing novel insight into the molecular mechanisms of the pathogenesis of DCM and suggesting potential implications for the prenatal prophylaxis and personalized treatment of this commonest primary myocardial disease.
authors.affiliation: Department of Emergency Medicine, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai 200233, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Department of Cardiology, Yantaishan Hospital, Yantai, Shandong 264001, P.R. China.
authors.forename: Lan
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Emergency Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
authors.forename: Jin-Qi
authors.initials: JQ
authors.lastname: Jiang
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
authors.forename: Wei-Feng
authors.initials: WF
authors.lastname: Jiang
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
authors.forename: Yi-Qing
authors.initials: YQ
authors.lastname: Yang
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
authors.forename: Xing-Biao
authors.initials: XB
authors.lastname: Qiu
mesh_terms: D000595:Amino Acid Sequence; D009320:Atrial Natriuretic Factor / Q000235:genetics*; D001483:Base Sequence; D002311:Cardiomyopathy, Dilated / Q000235:genetics*; D005260:Female; D050991:GATA4 Transcription Factor / Q000235:genetics*; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D020825:T-Box Domain Proteins / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human; D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5; D009320:Atrial Natriuretic Factor