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GATA 4 Loss‐of‐Function Mutations Underlie Familial Tetralogy of Fallot
Author(s) -
Yang YiQing,
Gharibeh Lara,
Li RuoGu,
Xin YuanFeng,
Wang Juan,
Liu ZhongMin,
Qiu XingBiao,
Xu YingJia,
Xu Lei,
Qu XinKai,
Liu Xu,
Fang WeiYi,
Huang RiTai,
Xue Song,
Nemer Georges
Publication year - 2013
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22434
Subject(s) - biology , genetics , missense mutation , proband , penetrance , gata4 , mutation , loss function , tetralogy of fallot , gene , phenotype , heart disease , medicine , transcription factor
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 GATA 4 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 GATA 4 mutants were consistently associated with diminished DNA ‐binding affinity and decreased transcriptional activity. Furthermore, the N285S mutation completely disrupted the physical interaction between GATA 4 and TBX 5. To our knowledge, this report associates GATA 4 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 .