International Journal of Medical Sciences

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14 December 2017

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Int J Med Sci 2014; 11(6):554-563. doi:10.7150/ijms.8407

Research Paper

Mutational Spectrum of the NKX2-5 Gene in Patients with Lone Atrial Fibrillation

Hong Yu1#, Jia-Hong Xu1#, Hao-Ming Song1#, Lan Zhao2#, Wen-Jun Xu1, Juan Wang1, Ruo-Gu Li3, Lei Xu3, Wei-Feng Jiang3, Xing-Biao Qiu3, Jin-Qi Jiang4, Xin-Kai Qu3, Xu Liu3, Wei-Yi Fang3, Jin-Fa Jiang1✉, Yi-Qing Yang3,5,6✉

1. Department of Cardiology, Tongji Hospital, Tongji University School of Medicine, 389 Xincun Road, Shanghai 200065, China;
2. Department of Cardiology, Yantaishan Hospital, 91 Jiefang Road, Yantai 264001, Shandong, China;
3. Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai 200030, China;
4. Department of Emergency, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai 200030, China;
5. Department of Cardiovascular Research Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai 200030, China;
6. Department of Central Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai 200030, China.
# These authors contributed equally to this work.

Abstract

Atrial fibrillation (AF) is the most common form of sustained cardiac arrhythmia in humans and is responsible for substantial morbidity and mortality worldwide. Emerging evidence indicates that abnormal cardiovascular development is involved in the pathogenesis of AF. In this study, the coding exons and splice sites of the NKX2-5 gene, which encodes a homeodomain-containing transcription factor essential for cardiovascular genesis, were sequenced in 146 unrelated patients with lone AF as well as the available relatives of the mutation carriers. A total of 700 unrelated ethnically matched healthy individuals used as controls were genotyped. The disease-causing potential of the identified NKX2-5 variations was predicted by MutationTaster and PolyPhen-2. The functional characteristics of the mutant NKX2-5 proteins were analyzed using a dual-luciferase reporter assay system. As a result, two heterozygous NKX2-5 mutations, including a previously reported p.E21Q and a novel p.T180A mutation, were identified in two families with AF transmitted in an autosomal dominant pattern. The mutations co-segregated with AF in the families with complete penetrance. The detected substitutions, which altered the amino acids highly conserved evolutionarily across species, were absent in 700 control individuals and were both predicted to be causative. Functional analyses demonstrated that the NKX2-5 mutants were associated with significantly decreased transcriptional activity compared with their wild-type counterpart. The findings expand the spectrum of NKX2-5 mutations linked to AF and provide additional evidence that dysfunctional NKX2-5 may confer vulnerability to AF, suggesting the potential benefit for the early prophylaxis and personalized treatment of AF.

Keywords: Atrial fibrillation, Transcription factor, NKX2-5, Molecular genetics, Mutation.

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) License. See http://ivyspring.com/terms for full terms and conditions.
How to cite this article:
Yu H, Xu JH, Song HM, Zhao L, Xu WJ, Wang J, Li RG, Xu L, Jiang WF, Qiu XB, Jiang JQ, Qu XK, Liu X, Fang WY, Jiang JF, Yang YQ. Mutational Spectrum of the NKX2-5 Gene in Patients with Lone Atrial Fibrillation. Int J Med Sci 2014; 11(6):554-563. doi:10.7150/ijms.8407. Available from http://www.medsci.org/v11p0554.htm