Premium
Functionally significant, novel GATA4 variants are frequently associated with Tetralogy of Fallot
Author(s) -
Dixit Ritu,
Narasimhan Chitra,
Balekundri Vijyalakshmi I.,
Agrawal Damyanti,
Kumar Ashok,
Mohapatra Bhagyalaxmi
Publication year - 2018
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.23620
Subject(s) - gata4 , biology , transactivation , zinc finger , sanger sequencing , tetralogy of fallot , genetics , proband , transcription factor , microbiology and biotechnology , medicine , heart disease , dna , mutation , dna sequencing , gene
Transcription factor GATA4 is known to play crucial role during heart development, regulating expression of several other key cardiogenic factors. Various GATA4 mutations are reported in familial as well as sporadic cases of congenital heart defects (CHDs). To estimate the prevalence and pathogenic potential of GATA4 variants in our CHD cohort, we have screened 285 CHD cases along with 200 controls by Sanger sequencing and identified 9 genetic variants (c.23C>A; p.Ala8Asp, c.25G>A; p.Ala9Thr, c.223G>T; p.Ala75Ser, c.383A>T; p.Glu128Val, c.397A>T; p.Ser133Cys, c.682T>A; p.Trp228Arg, c.1064C>G; p.Thr355Ser, c.1073G>C; p.Ser358Thr, and c.1220C>A; p.Pro407Gln) in 22 unrelated CHD probands (frequency:7.72%). Five of these are novel and located in the N‐terminal transactivation domain (TAD) and first zinc finger domain. Majority C‐terminal domain variants are polymorphic. Two of the TAD variants p.Glu128Val, p.Ser133Cys, and a first zinc finger variant p.Trp228Arg, impair combinatorial synergy of NKX2‐5, SRF, and TBX5, suggesting potential role of these domains in GATA4 interactions with these factors. Decreased DNA‐binding affinity with EMSA also supports this observation. Homology modeling and tertiary structure comparison show conformational changes in these variants. Interestingly, GATA4 variants are more frequently associated with ToF (45%; P = 0.0046) and PS (22.7%; P < 0.0001) in spite of abundance of septal defects in our study cohort.