Int J Med Sci 2016; 13(1):60-67. doi:10.7150/ijms.13264 This issue
1. Department of Cardiology, Shanghai Eighth People's Hospital, 8 Caobao Road, Shanghai 200235, China;
2. Department of Internal Medicine, Huajing Community Health Service Center of Xu Hui Distric, 180 Jianhua Road, Shanghai 200231, China;
3. Department of Pediatrics, Tongji Hospital, Tongji University School of Medicine, 389 Xincun Road, Shanghai 200065, China;
4. Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai 200030, China;
5. Department of Cardiovascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China;
6. Department of Cardiovascular Research Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai 200030, China;
7. Department of Central Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai 200030, China.
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.
Keywords: Atrial fibrillation, Genetics, Transcription factor, TBX5, Reporter gene assay.