title: GATA4 loss-of-function mutations underlie familial tetralogy of fallot.
abstract: Tetralogy of Fallot (TOF) represents the most common form of cyanotic congenital heart disease and accounts for significant morbidity and mortality in humans. Emerging evidence has implicated genetic defects in the pathogenesis of TOF. However, TOF is genetically heterogeneous and the genetic basis for TOF in most patients remains unclear. In this study, the GATA4 gene were sequenced in 52 probands with familial TOF, and three novel heterozygous mutations, including A9P and L51V both located in the putative first transactivational domain and N285S in the C-terminal zinc finger, were identified in three probands, respectively. Genetic analysis of the pedigrees demonstrated that in each family the mutation cosegregated with TOF with complete penetrance. The missense mutations were absent in 800 control chromosomes and the altered amino acids were highly conserved evolutionarily. Functional analysis showed that the GATA4 mutants were consistently associated with diminished DNA-binding affinity and decreased transcriptional activity. Furthermore, the N285S mutation completely disrupted the physical interaction between GATA4 and TBX5. To our knowledge, this report associates GATA4 loss-of-function mutations with familial TOF for the first time, providing novel insight into the molecular mechanism involved in TOF and suggesting potential implications for the early prophylaxis and allele-specific therapy of TOF.
authors.affiliation: Department of Cardiology and Cardiovascular Research, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Yi-Qing
authors.initials: YQ
authors.lastname: Yang
authors.forename: Lara
authors.initials: L
authors.lastname: Gharibeh
authors.forename: Ruo-Gu
authors.initials: RG
authors.lastname: Li
authors.forename: Yuan-Feng
authors.initials: YF
authors.lastname: Xin
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.forename: Zhong-Min
authors.initials: ZM
authors.lastname: Liu
authors.forename: Xing-Biao
authors.initials: XB
authors.lastname: Qiu
authors.forename: Ying-Jia
authors.initials: YJ
authors.lastname: Xu
authors.forename: Lei
authors.initials: L
authors.lastname: Xu
authors.forename: Xin-Kai
authors.initials: XK
authors.lastname: Qu
authors.forename: Xu
authors.initials: X
authors.lastname: Liu
authors.forename: Wei-Yi
authors.initials: WY
authors.lastname: Fang
authors.forename: Ri-Tai
authors.initials: RT
authors.lastname: Huang
authors.forename: Song
authors.initials: S
authors.lastname: Xue
authors.forename: Georges
authors.initials: G
authors.lastname: Nemer
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D000595:Amino Acid Sequence; D002467:Cell Nucleus / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D050991:GATA4 Transcription Factor / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011485:Protein Binding; D021381:Protein Transport; D016415:Sequence Alignment; D020825:T-Box Domain Proteins / Q000378:metabolism; D013771:Tetralogy of Fallot / Q000175:diagnosis / Q000235:genetics*; D014158:Transcription, Genetic; D055815:Young Adult
chemical_list: D050991:GATA4 Transcription Factor; D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5
keywords: GATA4; congenital heart disease; tetralogy of Fallot; transcription factor