PUBLICATION
TBX5 mutations contribute to early-onset atrial fibrillation in Chinese and Caucasians
- Authors
- Ma, J.F., Yang, F., Mahida, S.N., Zhao, L., Chen, X., Zhang, M.L., Sun, Z., Yao, Y., Zhang, Y.X., Zheng, G.Y., Dong, J., Feng, M.J., Zhang, R., Sun, J., Li, S., Wang, Q.S., Cao, H., Benjamin, E.J., Ellinor, P.T., Li, Y.G., Tian, X.L.
- ID
- ZDB-PUB-160115-10
- Date
- 2016
- Source
- Cardiovascular research 109(3): 442-50 (Journal)
- Registered Authors
- Dong, Jie (Janet), Ellinor, Patrick, Yang, Fan
- Keywords
- ANP, Atrial fibrillation, Connexin, Mutation, TBX5
- MeSH Terms
-
- Adult
- Age of Onset
- Aged
- Asian People
- Atrial Fibrillation/genetics*
- Atrial Fibrillation/metabolism
- Connexins/genetics
- Female
- Genetic Predisposition to Disease*
- Homeodomain Proteins/genetics
- Humans
- Middle Aged
- Mutation/genetics*
- Mutation, Missense/genetics
- Pregnancy
- T-Box Domain Proteins/genetics*
- T-Box Domain Proteins/metabolism
- Transcription Factors/metabolism
- White People
- PubMed
- 26762269 Full text @ Cardiovasc. Res.
Citation
Ma, J.F., Yang, F., Mahida, S.N., Zhao, L., Chen, X., Zhang, M.L., Sun, Z., Yao, Y., Zhang, Y.X., Zheng, G.Y., Dong, J., Feng, M.J., Zhang, R., Sun, J., Li, S., Wang, Q.S., Cao, H., Benjamin, E.J., Ellinor, P.T., Li, Y.G., Tian, X.L. (2016) TBX5 mutations contribute to early-onset atrial fibrillation in Chinese and Caucasians. Cardiovascular research. 109(3):442-50.
Abstract
Aims Atrial fibrillation (AF) is a common arrhythmia with an important heritable aspect. The genetic factors underlying AF have not been fully elucidated.
Methods and results We screened six candidate genes (CAV1, KCNJ2, KCNQ1, NKX2.5, PITX2, and TBX5) for novel mutations in 139 patients of Chinese descent with early-onset AF and 576 controls. Four missense TBX5 mutations, p.R355C, p.Q376R, p.A428S, and p.S372L, were identified in evolutionarily conserved regions. We did not find any mutations in CAV1, KCNJ2, KCNQ1, NKX2.5, and PITX2. These mutations increased the expression of atrial natriuretic peptide (ANP) and connexin-40 (CX40) in the primarily cultured rat atrial myocytes, but did not alter the expression of cardiac structural genes, atrial myosin heavy chain-α (MHC-α) and myosin light chain-2α (MLC-2α). Over-expression of p.R355C developed an atrial arrhythmia suggestive of paroxysmal AF in the zebrafish model. In order to replicate our findings, we screened TBX5 in 527 early-onset AF cases from the Massachusetts General Hospital AF study. A novel TBX5 deletion (ΔAsp118, p.D118del) was identified, while no TBX5 mutations were identified in 1176 control subjects.
Conclusion Our results provide both genetic and functional evidence to support the contribution of TBX5 gene in the pathogenesis of AF. The potential mechanism of arrhythmia may be due in part to the disturbed expression of ANP and CX40.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping