title: GATA5 loss-of-function mutations associated with congenital bicuspid aortic valve.
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.
authors.affiliation: Department of Ultrasonics, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, P.R. China.
authors.forename: Lin-Mei
authors.initials: LM
authors.lastname: Shi
authors.affiliation: Department of Ultrasonics, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, P.R. China.
authors.forename: Ju-Wei
authors.initials: JW
authors.lastname: Tao
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
authors.forename: Xing-Biao
authors.initials: XB
authors.lastname: Qiu
authors.affiliation: Department of Cardiology, East Hospital, Tongji University School of Medicine, Shanghai 200120, P.R. China.
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
authors.forename: Fang
authors.initials: F
authors.lastname: Yuan
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
authors.forename: Lei
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
authors.forename: Hua
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
authors.forename: Ruo-Gu
authors.initials: RG
authors.lastname: Li
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
authors.forename: Ying-Jia
authors.initials: YJ
authors.lastname: Xu
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
authors.forename: Hong-Zhen
authors.initials: HZ
authors.lastname: Zheng
authors.affiliation: Department of Extracorporeal Circulation, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Cardiac Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
authors.forename: Xiao-Zhou
authors.initials: XZ
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
authors.forename: Xin-Kai
authors.initials: XK
authors.lastname: Qu
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
authors.forename: Yi-Qing
authors.initials: YQ
authors.lastname: Yang
mesh_terms: D000328:Adult; D001021:Aortic Valve / Q000002:abnormalities*; D000082882:Bicuspid Aortic Valve Disease; D005260:Female; D050992:GATA5 Transcription Factor / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006330:Heart Defects, Congenital / Q000235:genetics*; D006349:Heart Valve Diseases / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D055815:Young Adult
chemical_list: D050992:GATA5 Transcription Factor