title: TBX5 loss-of-function mutation contributes to atrial fibrillation and atypical Holt-Oram syndrome.
abstract: Previous genome-wide association studies have demonstrated that single nucleotide polymorphisms in T‑box (TBX)5 are associated with increased susceptibility to atrial fibrillation (AF), and a recent study has causally linked a TBX5 mutation to atypical Holt-Oram syndrome and paroxysmal AF. However, the prevalence and spectrum of TBX5 mutations in patients with AF remain to be elucidated. In the present study, a cohort of 190 unrelated patients with idiopathic AF were prospectively recruited, with 400 unrelated healthy individuals recruited as controls. The coding exons and flanking introns of the TBX5 gene were sequenced in the participants. The functional characteristics of the mutant TBX5 were delineated in contrast with its wild‑type counterpart using a dual‑luciferase reporter assay system. As a result, a novel heterozygous TBX5 mutation, p.P132S, was identified in an index patient with AF, with a mutational prevalence of ~0.53%. Genetic analysis of the proband's family showed that the mutation co‑segregated with AF, and was transmitted in an autosomal dominant pattern. The missense mutation was absent in the 800 control chromosomes, and the altered amino acid was completely evolutionarily conserved across species. Functional analyses revealed that the mutant TBX5 had significantly reduced transcriptional activity. Furthermore, the mutation markedly decreased the synergistic activation between TBX5 and NK2 homeobox 5, another transcription factor which has been causatively linked to AF. The present study was the first, to the best of our knowledge, to report on the association between a TBX5 loss‑of‑function mutation and increased susceptibility to AF. These results provide novel insight into the molecular mechanism underpinning AF, and have potential implications in the development of novel prophylactic and therapeutic strategies for AF, the most common form of sustained cardiac arrhythmia.
authors.affiliation: Department of Emergency Medicine, Shanghai Gongli Hospital, Second Military Medical University, Shanghai 200135, P.R. China.
authors.forename: Dong-Feng
authors.initials: DF
authors.lastname: Guo
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
authors.forename: Ruo-Gu
authors.initials: RG
authors.lastname: Li
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
authors.forename: Fang
authors.initials: F
authors.lastname: Yuan
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
authors.forename: Hong-Yu
authors.initials: HY
authors.lastname: Shi
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
authors.forename: Xu-Min
authors.initials: XM
authors.lastname: Hou
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
authors.forename: Xin-Kai
authors.initials: XK
authors.lastname: Qu
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
authors.forename: Ying-Jia
authors.initials: YJ
authors.lastname: Xu
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
authors.forename: Xu
authors.initials: X
authors.lastname: Liu
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: 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: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D001281:Atrial Fibrillation / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000378:metabolism; D006344:Heart Septal Defects, Atrial / Q000235:genetics* / Q000378:metabolism; D000072576:Homeobox Protein Nkx-2.5 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D038061:Lower Extremity Deformities, Congenital / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D011446:Prospective Studies; D020825:T-Box Domain Proteins / Q000235:genetics* / Q000378:metabolism; D038062:Upper Extremity Deformities, Congenital / Q000235:genetics* / Q000378:metabolism
chemical_list: D000072576:Homeobox Protein Nkx-2.5; D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5