Prevalence and Spectrum of TBX5 Mutation in Patients with Lone Atrial Fibrillation

Abstract

Atrial fibrillation (AF), the most common type of cardiac rhythm disturbance encountered in clinical practice, is associated with substantially increased morbidity and mortality. Aggregating evidence demonstrates that abnormal cardiovascular development is involved in the pathogenesis of AF. A recent study has revealed that the TBX5 gene, which encodes a T-box transcription factor key to cardiovascular development, was associated with AF and atypical Holt-Oram syndrome. However, the prevalence and spectrum of TBX5 mutation in patients with lone AF remain unclear. In this study, the coding regions and splicing junction sites of TBX5 were sequenced in 192 unrelated patients with lone AF and 300 unrelated ethnically-matched healthy individuals used as controls. The causative potential of the identified TBX5 variation was evaluated by MutationTaster and PolyPhen-2. The functional effect of the mutant TBX5 was assayed by using a dual-luciferase reporter assay system. As a result, a novel heterozygous TBX5 mutation, p.H170D, was identified in a patient, with a mutational prevalence of approximately 0.52%. This mutation, which was absent in the 300 control individuals, altered the amino acid completely conserved evolutionarily across species, and was predicted to be disease-causing. Functional deciphers showed that the mutant TBX5 was associated with significantly reduced transcriptional activity when compared with its wild-type counterpart. Furthermore, the mutation significantly decreased the synergistic activation between TBX5 and NKX2-5 or GATA4. The findings expand the mutational spectrum of TBX5 linked to AF and provide new evidence that dysfunctional TBX5 may contribute to lone AF.

A SHOX2 loss-of-function mutation underlying familial atrial fibrillation

“…The study participants experienced a comprehensive clinical investigation, including individual and familial history, detailed physical examination, standard 12-lead electrocardiogram and cardiac echocardiography as well as review of medical records. Diagnosis and classification of AF was made as previously described 14 . Subjects with hypertension, coronary heart disease, valvular heart disease, congenital heart disease, congestive heart failure, metabolic disorders, or any other recognized risk factor of AF were excluded from the study.…”

A Tbx5 Nonsense Mutation in Siblings With Divergent Phenotypes Associated With Isolated Septal Defects

“…The reason for this diverse phenotype following the same mutation is still unclear. The cross-species alignment of TBX5 protein showed that the altered tryptophan residue is evolutionarily conserved throughout the vertebrates, indicating its functional importance [22]. The understanding of the genetic mutations is an important aspect in deciphering the consequential clinical phenotypes [23,24].…”

A novel TBX5 mutation predisposes to familial cardiac septal defects and atrial fibrillation as well as bicuspid aortic valve

“…Ma et al, (2016) identified multiple loss-of-function mutations in TBX5 in multiple patients affected with AF. Wang et al, (2016) found a novel loss-of-function mutation in TBX5 in a case with AF. Guo et al, (2016) uncovered a new TBX5 loss-of-function mutation in an index patient with idiopathic AF.…”