A novel mutation of GATA4 (K319E) is responsible for familial atrial septal defect and pulmonary valve stenosis

Xiang, Rong; Fan, Liang‐Liang; Huang, Hao; Cao, Bangwei; Li, Xiangping; Peng, Daoquan; Xia, Kun

doi:10.1016/j.gene.2013.10.028

Cited by 57 publications

(43 citation statements)

References 28 publications

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“…1 B). This newly identified mutation was neither found in the parents or in other unaffected family members of our patient, nor in our 200 controls [Xiang et al, 2014]. What is more, this mutation has not been reported in the dbSNP or Exome Variant Server database as well.…”

Section: Resultsmentioning

confidence: 53%

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A Novel ZRS Mutation in a Chinese Patient with Preaxial Polydactyly and Triphalangeal Thumb

Wu¹,

Guo

Fan³

et al. 2016

Cytogenet Genome Res

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Preaxial polydactyly (PPD; OMIM 603596), which is characterized as having supernumerary fingers, is an unusual congenital hand abnormality. Triphalangeal thumb (TPT; OMIM 190600) is identified by an extra phalangeal bone and is often found in association with PPD. When in combination, the disease is referred to as PPD type II (PPD II; OMIM 174500). Previous studies have demonstrated that variations in the zone of polarizing activity regulatory sequence (ZRS; chr7:156,583,796-156,584,569; hg19) region are associated with PPD II. In this study, our patient was diagnosed with PPD II, having bilateral thumb duplication and unilateral TPT (on the right hand). Further investigation of possible causative genes identified a de novo heterozygous ZRS mutation (ZRS 428T>A). This novel mutation was neither found in 200 normal controls nor reported in online databases. Moreover, the bioinformatics program Genomic Evolutionary Rate Profiling (GERP) revealed this site (ZRS428) to be evolutionarily highly conserved, and the 428T>A point mutation was predicted to be deleterious by MutationTaster. In conclusion, the affected individual shows bilateral thumb duplication, but unilateral TPT making this case special. Thus, our findings not only further support the important role of ZRS in limb morphogenesis and expand the spectrum of ZRS mutations, but also emphasize the significance of genetic diagnosis and counseling of families with digit number and identity alterations as well.

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Section: Resultsmentioning

confidence: 53%

“…Sequences of the PCR products were determined using the ABI 3100 Genetic Analyzer (ABI, Foster City, Calif., USA) as previously described [Xiang et al, 2014].…”

Section: Mutation Sequencingmentioning

confidence: 99%

A Novel ZRS Mutation in a Chinese Patient with Preaxial Polydactyly and Triphalangeal Thumb

Wu¹,

Guo

Fan³

et al. 2016

Cytogenet Genome Res

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“…* To whom correspondence should be addressed at: Center for Cardiovascular and Pulmonary Research and The Heart Center, Nationwide Children's Hospital, Room WB4221 Columbus, OH 43205, USA. Tel: +1 6143555740; Fax: +1 6143555725; Email: vidu.garg@nationwidechildrens.org (12,13). Furthermore, Gata4 and Tbx5 demonstrated a physical interaction in vitro, synergistically activated downstream target genes and exhibited a genetic interaction in vivo, suggesting that these transcription factors regulated a gene program critical for cardiac septation (9,14,15).…”

Section: Introductionmentioning

confidence: 99%

Disruption of myocardial Gata4 and Tbx5 results in defects in cardiomyocyte proliferation and atrioventricular septation

Misra

Chang

Basu

et al. 2014

Human Molecular Genetics

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Mutations in GATA4 and TBX5 are associated with congenital heart defects in humans. Interaction between GATA4 and TBX5 is important for normal cardiac septation, but the underlying molecular mechanisms are not well understood. Here, we show that Gata4 and Tbx5 are co-expressed in the embryonic atria and ventricle, but after E15.5, ventricular expression of Tbx5 decreases. Co-localization and co-immunoprecipitation studies demonstrate an interaction of Gata4 and Tbx5 in the developing atria and ventricles, but the ventricular interaction declines after E14.5. Gata4 1/2 ;Tbx5 1/2 mouse embryos display decreased atrial and ventricular myocardial thickness at E11.5, prior to cardiac septation. To determine the cell lineage in which the interaction was functionally significant in vivo, mice heterozygous for Gata4 in the myocardium or endocardium and heterozygous for Tbx5 (Gata4 MyoDel/wt ;Tbx5 1/2 and Gata4EndoDel/wt ;Tbx5 1/2 , respectively) were generated. Gata4MyoDel/wt ; Tbx5 1/2 mice displayed embryonic lethality, thin myocardium with reduced cell proliferation, and atrioventricular septation defects similar to Gata4;Tbx5 compound heterozygotes while Gata4EndoDel/wt ;Tbx5 1/ 2 embryos were normal. Cdk4 and Cdk2, cyclin-dependent kinases required for myocardial development and septation were reduced in Gata4 1/2 ;Tbx5 1/2 hearts. Cdk4 is a known direct target of Gata4 and the regulation of Cdk2 in the developing heart has not been studied. Chromatin immunoprecipitation and transactivation studies demonstrate that Gata4 and Tbx5 directly regulate Cdk4 while only Tbx5 activates Cdk2 expression. These findings highlight the mechanisms by which disruption of the Gata4 and Tbx5 interaction in the myocardium contributes to cardiac septation defects in humans.

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“…[7] Further evidence of the gene's relevance is that certain mutations in this gene are linked to congenital heart disease, hypoplasia of the ventricular myocardium, and cardiac septal defects. [8] Gene expression studies for the gene have found that alterations in the expression have been linked to several cancers. [9] …”

Section: Gata4mentioning

confidence: 99%

SNP Analysis, Genome Wide Association Studies and Pharmacogenetic implications of Acute Myocardial Infarction

Ganugapati¹,

Mathur²,

Chamarty³

et al. 2017

IJCA

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A novel mutation of GATA4 (K319E) is responsible for familial atrial septal defect and pulmonary valve stenosis

Cited by 57 publications

References 28 publications

A Novel ZRS Mutation in a Chinese Patient with Preaxial Polydactyly and Triphalangeal Thumb

A Novel ZRS Mutation in a Chinese Patient with Preaxial Polydactyly and Triphalangeal Thumb

Disruption of myocardial Gata4 and Tbx5 results in defects in cardiomyocyte proliferation and atrioventricular septation

SNP Analysis, Genome Wide Association Studies and Pharmacogenetic implications of Acute Myocardial Infarction

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