International Journal of Medical Sciences

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16 November 2018

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Int J Med Sci 2018; 15(13):1564-1572. doi:10.7150/ijms.27424

Research Paper

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

Ning Li1*, Zhang-Sheng Wang2*, Xin-Hua Wang3*, Ying-Jia Xu2, Qi Qiao2, Xiu-Mei Li2, Ruo-Min Di2, Xiao-Juan Guo2,4, Ruo-Gu Li1, Min Zhang1, Xing-Biao Qiu1✉, Yi-Qing Yang2,4,5✉

1. Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai 200030, China
2. Department of Cardiology, The Fifth People′s Hospital of Shanghai, Fudan University, 801 Heqing Road, Shanghai 200240, China
3. Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai 200127, China
4. Department of Cardiovascular Research Laboratory, The Fifth People′s Hospital of Shanghai, Fudan University, 801 Heqing Road, Shanghai 200240, China
5. Department of Central Laboratory, The Fifth People′s Hospital of Shanghai, Fudan University, 801 Heqing Road, Shanghai 200240, China
* These two authors contributed equally to this work.


Atrial fibrillation (AF), as the most common sustained cardiac arrhythmia, is associated with substantially increased morbidity and mortality. Aggregating evidence demonstrates that genetic defects play a crucial role in the pathogenesis of AF, especially in familial AF. Nevertheless, AF is of pronounced genetic heterogeneity, and in an overwhelming majority of cases the genetic determinants underlying AF remain elusive. In the current study, 162 unrelated patients with familial AF and 238 unrelated healthy individuals served as controls were recruited. The coding exons and splicing junction sites of the SHOX2 gene, which encodes a homeobox-containing transcription factor essential for proper development and function of the cardiac conduction system, were sequenced in all study participants. The functional effect of the mutant SHOX2 protein was characterized with a dual-luciferase reporter assay system. As a result, a novel heterozygous SHOX2 mutation, c.580C>T or p.R194X, was identified in an index patient, which was absent from the 476 control chromosomes. Genetic analysis of the proband's pedigree revealed that the nonsense mutation co-segregated with AF in the family with complete penetrance. Functional assays demonstrated that the mutant SHOX2 protein had no transcriptional activity compared with its wild-type counterpart. In conclusion, this is the first report on the association of SHOX2 loss-of-function mutation with enhanced susceptibility to familial AF, which provides novel insight into the molecular mechanism underpinning AF, suggesting potential implications for genetic counseling and individualized management of AF patients.

Keywords: Atrial fibrillation, Molecular genetics, Transcription factor, SHOX2, Reporter gene assay

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license ( See for full terms and conditions.
How to cite this article:
Li N, Wang ZS, Wang XH, Xu YJ, Qiao Q, Li XM, Di RM, Guo XJ, Li RG, Zhang M, Qiu XB, Yang YQ. A SHOX2 loss-of-function mutation underlying familial atrial fibrillation. Int J Med Sci 2018; 15(13):1564-1572. doi:10.7150/ijms.27424. Available from