Novel GATA6 Mutations Associated with Congenital Ventricular Septal Defect or Tetralogy of Fallot

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Abstract. Atrial fibrillation (AF) represents the most common form of sustained cardiac arrhythmia and accounts for substantial morbidity and mortality. Increasing evidence demonstrates that abnormal cardiovascular development is involved in the pathogenesis of AF. In this study, the coding exons and splice sites of the NKX2.5 gene, which encodes a homeodomain-containing transcription factor pivotal for normal cardiovascular morphogenesis, were sequenced in 110 unrelated index patients with familial AF. The available relatives of the mutation carrier and 200 unrelated ethnically-matched healthy individuals serving as controls were subsequently genotyped. The disease-causing potential of the identified NKX2.5 variation was predicted by MutationTaster. The functional characteristics of the mutant NKX2.5 protein were analyzed using a dual-luciferase reporter assay system. As a result, a novel heterozygous NKX2.5 mutation, p.F145S, was identified in a family with AF transmitted as an autosomal dominant trait, which co-segregated with AF in the family with complete penetrance. The detected substitution, which altered the amino acid completely conserved evolutionarily across species, was absent in 400 control chromosomes and was automatically predicted to be causative. Functional analysis demonstrated that the NKX2.5 mutant was associated with significantly decreased transcriptional activity compared with its wild-type counterpart. To the best of our knowledge, this is the first report on the association of the NKX2.5 lossof-function mutation with increased susceptibility to familial AF. The findings of the present study provide novel insights into the molecular mechanism underlying AF, suggesting the potential implications for the early prophylaxis and allelespecific therapy of AF.

Section: Discussionmentioning

confidence: 58%

A novel NKX2.5 loss-of-function mutation responsible for familial atrial fibrillation

Huang

Xue

et al. 2013

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“…In humans, mutations in GATA4 have been associated with various cardiac phenotypes, including congenital heart diseases, atrial fibrillation and DCM (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Similarly, genetic variations in GATA6 are also involved in the pathogenesis of congenital cardiovascular malformations and atrial fibrillation (26)(27)(28)(29)(30)(31)(32)(33)(34), rendering it justifiable to screen GATA6 as a prime candidate gene for DCM.…”

Section: Introductionmentioning

confidence: 99%

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

Zhao

Fang

et al. 2014

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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.

“…Cardiogenesis is a complex and dynamic biological process that requires the orchestration of cardiac cell commitment, differentiation, proliferation and migration, and both environmental and genetic risk factors may perturb this exquisite temporal and spatial cooperation, leading to a wide variety of CHD (15)(16)(17)(18)(19)(20)(21)(22). A growing body of evidence underscores the key role of cardiac transcription factors in Novel PITX2c loss-of-function mutations associated with complex congenital heart disease DONG WEI 1 , XIAO-HUI GONG 1 embryonic cardiovascular morphogenesis, and a long list of mutations in the genes coding for cardiac transcription factors, including the NK and GATA families, have been associated with CHD (23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41). However, CHD is a genetically heterogeneous disease and the genetic defects responsible for CHD in the majority of patients remain unknown.…”

Section: Introductionmentioning

confidence: 99%

Novel PITX2c loss-of-function mutations associated with complex congenital heart disease

Wei

Gong

Qiu

et al. 2014

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Abstract. Congenital heart disease (CHD) is the most common form of birth defect in humans and is the leading non-infectious cause of infant mortality. Emerging evidence strongly suggests that genetic risk factors play an important role in the pathogenesis of CHD. However, CHD is of pronounced genetic heterogeneity, and the genetic defects responsible for CHD in an overwhelming majority of patients remain unclear. In this study, the entire coding region and splice junction sites of the PITX2c gene, which encodes a paired-like homeodomain transcription factor crucial for proper cardiovascular morphogenesis, was sequenced in 170 unrelated neonates with CHD. The available relatives of the mutation carriers and 200 unrelated ethnically matched healthy individuals were genotyped. The disease-causing potential of the PITX2c sequence variations was predicted by MutationTaster and PolyPhen-2. The functional effect of the mutations was characterized using a luciferase reporter assay system. As a result, 2 novel heterozygous PITX2c mutations, p.R91Q and p.T129S, were identified in 2 unrelated newborns with transposition of the great arteries and ventricular septal defect, respectively. A genetic scan of the pedigrees revealed that each mutation co-segregated with CHD transmitted in an autosomal dominant pattern with complete penetrance. The mutations, which altered the amino acids completely conserved evolutionarily, were absent in 400 normal chromosomes and were predicted to be causative.Functional analysis revealed that the PITX2c mutations were both associated with significantly diminished transcriptional activity compared with their wild-type counterpart. This study demonstrates the association between PITX2c loss-of-function mutations and the transposition of the great arteries and ventricular septal defect in humans, providing further insight into the molecular mechanisms responsible for CHD.