International Journal of Medical Sciences

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20 October 2017

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Int J Med Sci 2013; 10(10):1422-1429. doi:10.7150/ijms.6809

Research Paper

PITX2c Loss-of-Function Mutations Responsible for Congenital Atrial Septal Defects

Fang Yuan1#, Lan Zhao2#, Juan Wang3, Wei Zhang4, Xin Li5, Xing-Biao Qiu1, Ruo-Gu Li1, Ying-Jia Xu1, Lei Xu1, Xing-Kai Qu1, Wei-Yi Fang1✉, Yi-Qing Yang1,6 ✉

1. Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai 200030, China
2. Department of Cardiology, Yantaishan Hospital, 91 Jiefang Road, Yantai 264001, Shandong, China
3. Department of Cardiology, East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai 200120, China
4. Department of Cardiac Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai 200030, China
5. Department of Extracorporeal Circulation, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai 200030, China
6. Department of Cardiovascular Research, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai 200030, China
# Contributed equally to this work.

Abstract

Congenital heart disease (CHD) is the most common form of developmental anomaly and is the leading non-infectious cause of infant mortality. A growing body of evidence demonstrates that genetic risk factors are involved in the pathogenesis of CHD. However, CHD is a genetically heterogeneous disease and the genetic determinants for CHD in most patients remain unclear. In the present study, the entire coding region and splice junction sites of the PITX2c gene, which encodes a homeobox transcription factor crucial for normal cardiovascular genesis, was sequenced in 150 unrelated patients with various CHDs. The 200 unrelated control individuals were subsequently genotyped. The functional characteristics of the mutations were explored using a dual-luciferase reporter assay system. As a result, two novel heterozygous PITX2c mutations, p.H98Q and p.M119T, were identified in 2 unrelated patients with atrial septal defects, respectively. The variations were absent in 400 control chromosomes and the affected amino acids were completely conserved evolutionarily. The two variants were both predicted to be disease-causing by MutationTaster and PolyPhen-2, and the functional analysis revealed that the PITX2c mutants were consistently associated with significantly reduced transcriptional activity compared with their wild-type counterpart. These findings firstly link PITX2c loss-of-function mutations to atrial septal defects in humans, which provide novel insight into the molecular mechanism responsible for CHD, suggesting potential implications for the early prophylaxis and allele-specific treatment of CHD.

Keywords: Congenital heart disease, Atrial septal defect, Genetics, Transcription factor, PITX2c

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:
Yuan F, Zhao L, Wang J, Zhang W, Li X, Qiu XB, Li RG, Xu YJ, Xu L, Qu XK, Fang WY, Yang YQ. PITX2c Loss-of-Function Mutations Responsible for Congenital Atrial Septal Defects. Int J Med Sci 2013; 10(10):1422-1429. doi:10.7150/ijms.6809. Available from http://www.medsci.org/v10p1422.htm