TBX5 loss-of-function mutation contributes to atrial fibrillation and atypical Holt-Oram syndrome

Mol Med Rep. 2016 May;13(5):4349-56. doi: 10.3892/mmr.2016.5043. Epub 2016 Mar 24.

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.

Publication types

  • Clinical Trial
  • Multicenter Study

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Abnormalities, Multiple / metabolism
  • Adult
  • Atrial Fibrillation / genetics*
  • Atrial Fibrillation / metabolism
  • Cell Line
  • Female
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Heart Defects, Congenital / genetics*
  • Heart Defects, Congenital / metabolism
  • Heart Septal Defects, Atrial / genetics*
  • Heart Septal Defects, Atrial / metabolism
  • Homeobox Protein Nkx-2.5 / genetics
  • Homeobox Protein Nkx-2.5 / metabolism
  • Humans
  • Lower Extremity Deformities, Congenital / genetics*
  • Lower Extremity Deformities, Congenital / metabolism
  • Male
  • Middle Aged
  • Mutation, Missense*
  • Prospective Studies
  • T-Box Domain Proteins / genetics*
  • T-Box Domain Proteins / metabolism
  • Upper Extremity Deformities, Congenital / genetics*
  • Upper Extremity Deformities, Congenital / metabolism

Substances

  • Homeobox Protein Nkx-2.5
  • T-Box Domain Proteins
  • T-box transcription factor 5

Supplementary concepts

  • Holt-Oram syndrome