GATA5 loss-of-function mutations associated with congenital bicuspid aortic valve

Shi,Lin-Mei; Tao,Ju-Wei; Qiu,Xing-Biao; Wang,Juan; Yuan,Fang; Xu,Lei; Liu,Hua; Li,Ruo-Gu; Xu,Ying-Jia; Wang,Qian; Zheng,Hong-Zhen; Li,Xin; Wang,Xiao-Zhou; Zhang,Min; Qu,Xin-Kai; Yang,Yi-Qing

doi:10.3892/ijmm.2014.1700

GATA5 loss-of-function mutations associated with congenital bicuspid aortic valve

Authors:
- Lin-Mei Shi
- Ju-Wei Tao
- Xing-Biao Qiu
- Juan Wang
- Fang Yuan
- Lei Xu
- Hua Liu
- Ruo-Gu Li
- Ying-Jia Xu
- Qian Wang
- Hong-Zhen Zheng
- Xin Li
- Xiao-Zhou Wang
- Min Zhang
- Xin-Kai Qu
- Yi-Qing Yang
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Affiliations: Department of Ultrasonics, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, P.R. China, Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China, Department of Cardiology, East Hospital, Tongji University School of Medicine, Shanghai 200120, P.R. China, Department of Extracorporeal Circulation, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China, Department of Cardiac Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China
Published online on: March 14, 2014 https://doi.org/10.3892/ijmm.2014.1700
Pages: 1219-1226

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Abstract

Bicuspid aortic valve (BAV) is the most common form of congenital cardiovascular defect in humans worldwide and is responsible for substantial morbidity and mortality. Accumulating evidence has demonstated that genetic risk factors are involved in the pathogenesis of BAV. However, BAV is genetically heterogeneous and the genetic basis underlying BAV in a large number of patients remains unknown. In the present study, the coding regions and splice junction sites of the GATA5 gene, which codes for a zinc-finger transcription factor crucial for the normal development of the aortic valve, was sequenced initially in 110 unrelated patients with BAV. The available relatives of the mutation carriers and 200 unrelated healthy individuals used as controls were subsequently genotyped for GATA5. The functional effect of the mutations was characterized by using a luciferase reporter assay system. As a result, two novel heterozygous GATA5 mutations, p.Y16D and p.T252P, were identified in two families with autosomal dominant inheritance of BAV, respectively. The variations were absent in 400 control chromosomes and the altered amino acids were completely conserved evolutionarily. Functional assays revealed that the two GATA5 mutants were associated with significantly reduced transcriptional activity compared with their wild-type counterpart. To the best of our knowledge, this is the first study on the association of GATA5 loss-of-function mutations with enhanced susceptibility to BAV, providing novel insight into the molecular mechanism involved in human BAV and suggesting a potential role for the early prophylaxis and personalized treatment of this common congenital heart disease.

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