International Journal of Medical Sciences

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23 September 2017

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Int J Med Sci 2017; 14(4):323-332. doi:10.7150/ijms.17834

Research Paper

TBX20 loss-of-function mutation responsible for familial tetralogy of Fallot or sporadic persistent truncus arteriosus

Ri-Tai Huang1*, Juan Wang2*, Song Xue1, Xing-Biao Qiu3, Hong-Yu Shi3, Ruo-Gu Li3, Xin-Kai Qu3, Xiao-Xiao Yang3, Hua Liu3, Ning Li3, Yan-Jie Li3, Ying-Jia Xu3✉, Yi-Qing Yang3,4,5✉

1. Department of Cardiovascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai 200127, China;
2. Department of Cardiovascular Medicine, East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai 200120, China;
3. Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai 200030, China;
4. Department of Cardiovascular Research Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai 200030, China;
5. Department of Central Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai 200030, China.
* These two authors contributed equally to this work.

Abstract

Congenital heart disease (CHD), the most common form of developmental abnormality in humans, remains a leading cause of morbidity and mortality in neonates. Genetic defects have been recognized as the predominant causes of CHD. Nevertheless, CHD is of substantial genetic heterogeneity and the genetic defects underlying CHD in most cases remain unclear. In the current study, the coding regions and splicing junction sites of the TBX20 gene, which encodes a T-box transcription factor key to cardiovascular morphogenesis, were sequenced in 175 unrelated patients with CHD, and a novel heterozygous TBX20 mutation, p.K274X, was identified in an index patient with tetralogy of Fallot (TOF). Genetic analysis of the proband's available family members showed that his father, elder brother and son had also TOF. In addition, his father and elder brother had also atrial septal defect, and his niece had persistent truncus arteriosus and ventricular septal defect. Analysis of the pedigree revealed that the mutation co-segregated with CHD transmitted in an autosomal dominant fashion, with complete penetrance. The nonsense mutation, which was absent in the 800 control chromosomes, was predicted to produce a truncated protein with only the amino terminus and partial T-box domain left. Functional analyses by using a dual-luciferase reporter assay system showed that the mutant TBX20 lost the ability to transactivate the target gene ANF. Furthermore, the mutation reduced the synergistic activation between TBX20 and NKX2.5 as well as GATA4, two other transcriptional factors previously associated with various CHD, encompassing TOF. This study firstly links TBX20 loss-of-function mutation to familial TOF or sporadic persistent truncus arteriosus, providing novel insight into the molecular pathogenesis of CHD.

Keywords: Congenital heart disease, Tetralogy of Fallot, Genetics, Transcriptional factor, TBX20, Reporter gene assay

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.
How to cite this article:
Huang RT, Wang J, Xue S, Qiu XB, Shi HY, Li RG, Qu XK, Yang XX, Liu H, Li N, Li YJ, Xu YJ, Yang YQ. TBX20 loss-of-function mutation responsible for familial tetralogy of Fallot or sporadic persistent truncus arteriosus. Int J Med Sci 2017; 14(4):323-332. doi:10.7150/ijms.17834. Available from http://www.medsci.org/v14p0323.htm