Identification of intronic-splice site mutations in GATA4 gene in Indian patients with congenital heart disease

Bose, Divya; Vaigundan, D.; Shetty, Mitesh; Krishnappa, J; Kutty, A V Moideen

doi:10.1016/j.mrfmmm.2017.08.001

Cited by 16 publications

(10 citation statements)

References 36 publications

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“…In both mice and men, GATA4 is expressed in the somatic cell population of the developing heart and gonads and plays an essential role in their development ( 8 – 10 ). Human GATA4 mutations associated with cardiac malformations are described in numerous patients (Table S2 in Supplementary Material) and are located throughout the gene in the coding and non-coding sequence including 3′- and 5′-UTR ( 29 – 33 ). They comprise single nucleotide variants as well as deletions and duplications, which lead to missense/nonsense mutations or splicing errors and thus altered proteins or protein expression.…”

Section: Discussionmentioning

confidence: 99%

GATA4 Variants in Individuals With a 46,XY Disorder of Sex Development (DSD) May or May Not Be Associated With Cardiac Defects Depending on Second Hits in Other DSD Genes

et al. 2018

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Disorders of sex development (DSD) consist of a wide range of conditions involving numerous genes. Nevertheless, about half of 46,XY individuals remain genetically unsolved. GATA4 gene variants, mainly related to congenital heart defects (CHD), have also been recently associated with 46,XY DSD. In this study, we characterized three individuals presenting with 46,XY DSD with or without CHD and GATA4 variants in order to understand the phenotypical variability. We studied one patient presenting CHD and 46,XY gonadal dysgenesis, and two patients with a history of genetically unsolved 46,XY DSD, also known as male primary hypogonadism. Mutation analysis was carried out by candidate gene approach or targeted gene panel sequencing. Functional activity of GATA4 variants was tested in vitro on the CYP17 promoter involved in sex development using JEG3 cells. We found two novel and one previously described GATA4 variants located in the N-terminal zinc finger domain of the protein. Cys238Arg variant lost transcriptional activity on the CYP17 promoter reporter, while Trp228Cys and Pro226Leu behaved similar to wild type. These results were in line with bioinformatics simulation studies. Additional DSD variations, in the LRP4 and LHCGR genes, respectively, were identified in the two 46,XY individuals without CHD. Overall, our study shows that human GATA4 mutations identified in patients with 46,XY DSD may or may not be associated with CHD. Possible explanations for phenotypical variability may comprise incomplete penetrance, variable sensitivity of partner genes, and oligogenic mechanisms.

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Section: Discussionmentioning

confidence: 99%

GATA4 Variants in Individuals With a 46,XY Disorder of Sex Development (DSD) May or May Not Be Associated With Cardiac Defects Depending on Second Hits in Other DSD Genes

et al. 2018

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“…Furthermore, Bose et al. ( 16 ) revealed that mutations in non-coding regions of GATA4 could also affect the process during fetal heart development. At the CC level, the enriched terms for the two kinds of CHD were focused on adherents junction ( 17 ), contractile fiber part ( 18 ) and transcription factor complex ( 16 ).…”

Section: Resultsmentioning

confidence: 99%

“…( 16 ) revealed that mutations in non-coding regions of GATA4 could also affect the process during fetal heart development. At the CC level, the enriched terms for the two kinds of CHD were focused on adherents junction ( 17 ), contractile fiber part ( 18 ) and transcription factor complex ( 16 ). It has been shown that mutations occur in the whole coding region and splice junction sites of the PITX2c gene, which encodes paired-like home domain transcription factor 2 and is crucial for normal cardiovascular morphogenesis.…”

Section: Resultsmentioning

confidence: 99%

CHDGKB: a knowledgebase for systematic understanding of genetic variations associated with non-syndromic congenital heart disease

Yang

Liu

et al. 2020

Database

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Abstract Congenital heart disease (CHD) is one of the most common birth defects, with complex genetic and environmental etiologies. The reports of genetic variation associated with CHD have increased dramatically in recent years due to the revolutionary development of molecular technology. However, CHD is a heterogeneous disease, and its genetic origins remain inconclusive in most patients. Here we present a database of genetic variations for non-syndromic CHD (NS-CHD). By manually literature extraction and analyses, 5345 NS-CHD-associated genetic variations were collected, curated and stored in the public online database. The objective of our database is to provide the most comprehensive updates on NS-CHD genetic research and to aid systematic analyses of pathogenesis of NS-CHD in molecular level and the correlation between NS-CHD genotypes and phenotypes. Database URL: http://www.sysbio.org.cn/CHDGKB/

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“…However, studies correlating GATA4 mutations and CHD are meager in India, despite a higher prevalence of CHD (Bhardwaj et al, 2015). Five studies so far have been carried out to find association of already known GATA4 polymorphisms with CHD in Indian cohort (Borkar, Nayak, Shetty, Bhat, & Moka, 2017;Bose et al, 2017;Dinesh et al, 2011;Mattapally, Nizamuddin, Murthy, Thangaraj, & Banerjee, 2015;Ramegowda et al, 2007) which could not report any novel mutation.…”

Section: Discussionmentioning

confidence: 99%

Functionally significant, novelGATA4variants are frequently associated with Tetralogy of Fallot

Dixit

Narasimhan

Balekundri³

et al. 2018

Human Mutation

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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.

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Identification of intronic-splice site mutations in GATA4 gene in Indian patients with congenital heart disease

Cited by 16 publications

References 36 publications

GATA4 Variants in Individuals With a 46,XY Disorder of Sex Development (DSD) May or May Not Be Associated With Cardiac Defects Depending on Second Hits in Other DSD Genes

GATA4 Variants in Individuals With a 46,XY Disorder of Sex Development (DSD) May or May Not Be Associated With Cardiac Defects Depending on Second Hits in Other DSD Genes

CHDGKB: a knowledgebase for systematic understanding of genetic variations associated with non-syndromic congenital heart disease

Functionally significant, novelGATA4variants are frequently associated with Tetralogy of Fallot

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