title: Novel GATA6 mutations associated with congenital ventricular septal defect or tetralogy of fallot.
abstract: Congenital heart disease (CHD) is the most common form of developmental malformation and is the leading noninfectious cause of infant mortality. Emerging evidence indicates that genetic defects are involved in the pathogenesis of CHD. Nevertheless, CHD is genetically heterogeneous, and the molecular basis for CHD in a majority of patients remains unknown. In this study, the whole coding region of GATA6, a gene encoding a zinc-finger transcription factor crucial for normal cardiogenesis, was sequenced in 380 unrelated patients with CHD. The relatives of the index patients harboring the identified mutations and 200 unrelated control individuals were subsequently genotyped. The functional effect of the mutations was characterized using a luciferase reporter assay system. As a result, two novel heterozygous GATA6 mutations, p.D404Y and p.E460X, were identified in two families with ventricular septal defect and tetralogy of Fallot, respectively. The mutations co-segregated with CHD in the families with complete penetrance, and were absent in 400 control chromosomes. Functional analysis demonstrated that the mutated GATA6 proteins were associated with significantly decreased transactivational activity in comparison with their wild-type counterpart. These findings provide novel insight into the molecular mechanism implicated in CHD, suggesting potential implications for the early prophylaxis and personalized treatment of CHD.
authors.affiliation: Department of Cardiovascular Medicine, East Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.forename: Xue-Jiao
authors.initials: XJ
authors.lastname: Luo
authors.forename: Yuan-Feng
authors.initials: YF
authors.lastname: Xin
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Zhong-Min
authors.initials: ZM
authors.lastname: Liu
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.forename: Ruo-Gu
authors.initials: RG
authors.lastname: Li
authors.forename: Wei-Yi
authors.initials: WY
authors.lastname: Fang
authors.forename: Xiao-Zhou
authors.initials: XZ
authors.lastname: Wang
authors.forename: Yi-Qing
authors.initials: YQ
authors.lastname: Yang
mesh_terms: D000293:Adolescent; D000328:Adult; D044466:Asian People / Q000235:genetics; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D002681:China; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D050993:GATA6 Transcription Factor / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D057809:HEK293 Cells; D006330:Heart Defects, Congenital / Q000208:ethnology / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D010375:Pedigree; D013771:Tetralogy of Fallot / Q000208:ethnology / Q000235:genetics*; D055815:Young Adult
chemical_list: D050993:GATA6 Transcription Factor; C494759:GATA6 protein, human