Novel GATA5 loss-of-function mutations underlie familial atrial fibrillation

Gu, Jian-Yun; Xu, Iris; Yu, Inwu; Yang, Inho

doi:10.6061/clinics/2012(12)08

Cited by 33 publications

(21 citation statements)

References 38 publications

(37 reference statements)

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“…Similarly, mutations in other cardiac transcriptional factor genes, such as GATA4, GATA5, NKX2-5 and PITX2c, were also associated with atrial fibrillation (21)(22)(23)(46)(47)(48)(49)(50)(51)(52)(53). These observations support the hypothesis that a subset of atrial fibrillation may have developmental origin.…”

Section: Subject Informationsupporting

confidence: 74%

GATA6 loss-of-function mutations contribute to familial dilated cardiomyopathy

Zhao

Fang

et al. 2014

International Journal of Molecular Medicine

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Abstract. Dilated cardiomyopathy (DCM), the most prevalent form of primary heart muscle disease, is the third most common cause of heart failure and the most frequent reason for cardiac transplantation. Mounting evidence has demonstrated that genetic risk factors are crucial in the pathogenesis of DCM. However, DCM is genetically heterogeneous, and the genetic basis of DCM in a large majority of cases remains unclear. In the current study, the coding exons and flanking introns of the GATA6 gene, which encodes a zinc-finger transcription factor essential for cardiogenesis, was sequenced in 140 unrelated patients with DCM, and two novel heterozygous mutations, p.C447Y and p.H475R, were identified in two index patients with DCM, respectively. Analysis of the pedigrees showed that in each family the mutation co-segregated with DCM transmitted in an autosomal-dominant pattern, with complete penetrance. The missense mutations were absent in 400 control chromosomes and predicted to be disease-causing by MutationTaster or probably damaging by PolyPhen-2. The alignment of multiple GATA6 proteins across species revealed that the altered amino acids were completely conserved evolutionarily. The functional assays showed that the mutated GATA6 proteins were associated with significantly reduced transcriptional activation in comparison with their wild-type counterpart. To the best of our knowledge, this is the first study on the association of GATA6 loss-of-function mutations with enhanced susceptibility to familial DCM, which provides novel insight into the molecular mechanism of DCM and suggests potential implications for the antenatal prophylaxis and allele-specific treatment of DCM.

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Section: Subject Informationsupporting

confidence: 74%

GATA6 loss-of-function mutations contribute to familial dilated cardiomyopathy

Zhao

Fang

et al. 2014

International Journal of Molecular Medicine

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“…Our largely pediatric cohort limited our ability to explore genotype-phenotype correlations involving advanced valvular dysfunction and/or aortopathy. Interestingly, GATA5 variants have been reported in patients with tetralogy of Fallot, ventricular septal defects, and familial atrial fibrillation, but further studies are needed to investigate a potential role for GATA5 in isolated cases of coarctation of the aorta (17–19). …”

Section: Discussionmentioning

confidence: 99%

Rare GATA5 sequence variants identified in individuals with bicuspid aortic valve

et al. 2014

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Background Bicuspid aortic valve (BAV) is the most common congenital heart defect (CHD) and has a proposed genetic etiology. BAV is categorized by cusp fusion with Right-Left (R-L) cusp fusion being associated with additional CHD and Right-Noncoronary cusp (R-NC) fusion being associated with aortic valve dysfunction. Loss of murine Gata5, which encodes a cardiac transcription factor, results in a partially penetrant R-NC BAV, and we hypothesize that mutations in GATA5 are associated with R-NC BAV in humans. Methods A cohort of 78 BAV patients (50 with isolated BAV and 28 with associated aortic coarctation) was analyzed using Sanger sequencing to identify GATA5 sequence variants. Biochemical assays were performed to identify functional deficits of identified sequence variants. Results We identified two rare heterozygous non-synonymous variants, p.Gln3Arg and p.Leu233Pro, for a frequency of 2.6% (2/78). Both individuals with non-synonymous variants had BAV and aortic coarctation, one R-L and one R-NC subtype. Of the non-synonymous variants, only p.Gln3Arg demonstrated decreased transcriptional activity in vitro. Conclusions Rare sequence variants in GATA5 are associated with human BAV. Our findings suggest a genotype-phenotype correlation in regards to associated CHD but not cusp fusion.

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“…Peripheral venous blood samples were prepared, and clinical data including medical records, electrocardiograms, and echocardiography reports were collected. The study subjects were clinically classified using a consistently applied set of definitions (11,23). …”

Section: Methodsmentioning

confidence: 99%

Prevalence and spectrum of Nkx2.5 mutations associated with idiopathic atrial fibrillation

Xie¹,

Chang²,

Xu³

et al. 2013

Clinics

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OBJECTIVE:The aim of this study was to evaluate the prevalence and spectrum of Nkx2.5 mutations associated with idiopathic atrial fibrillation (AF).METHODS:A cohort of 136 unrelated patients with idiopathic atrial fibrillation and 200 unrelated, ethnically matched healthy controls were enrolled. The coding exons and splice junctions of the Nkx2.5 gene were sequenced in 136 atrial fibrillation patients, and the available relatives of mutation carriers and 200 controls were subsequently genotyped for the identified mutations. The functional characteristics of the mutated Nkx2.5 gene were analyzed using a dual-luciferase reporter assay system.RESULTS:Two novel heterozygous Nkx2.5 mutations (p.N19D and p.F186S) were identified in 2 of the 136 unrelated atrial fibrillation cases, with a mutational prevalence of approximately 1.47%. These missense mutations co-segregated with atrial fibrillation in the families and were absent in the 400 control chromosomes. Notably, 2 mutation carriers also had congenital atrial septal defects and atrioventricular block. Multiple alignments of the Nkx2.5 protein sequences across various species revealed that the altered amino acids were completely conserved evolutionarily. Functional analysis demonstrated that the mutant Nkx2.5 proteins were associated with significantly reduced transcriptional activity compared to their wild-type counterpart.CONCLUSION:These findings associate the Nkx2.5 loss-of-function mutation with atrial fibrillation and atrioventricular block and provide novel insights into the molecular mechanism involved in the pathogenesis of atrial fibrillation. These results also have potential implications for early prophylaxis and allele-specific therapy of this common arrhythmia.

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Novel GATA5 loss-of-function mutations underlie familial atrial fibrillation

Cited by 33 publications

References 38 publications

GATA6 loss-of-function mutations contribute to familial dilated cardiomyopathy

GATA6 loss-of-function mutations contribute to familial dilated cardiomyopathy

Rare GATA5 sequence variants identified in individuals with bicuspid aortic valve

Prevalence and spectrum of Nkx2.5 mutations associated with idiopathic atrial fibrillation

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