A novel GATA5 loss-of-function mutation underlies lone atrial fibrillation

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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: 84%

Section: Introductionmentioning

confidence: 93%

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

Huang

Xue

et al. 2013

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“…The primer pairs used to amplify the coding exons and exon-intron boundaries of the GATA5 gene were described in a previous study (46). Polymerase chain reaction (PCR) was carried out in Veriti Thermal Cycler (Applied Biosystems, Foster City, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

“…Thus it is obvious that cardiogenesis is a complex and dynamic process, which requires the harmonious orchestration of cardiac cell commitment, differentiation, proliferation and migration, and both environmental and genetic risk factors may disrupt the finely regulated biological process, resulting in CHD (12)(13)(14). Mounting evidence has demonstrated that an evolutionarily conserved network of transcription factors connecting signaling pathways with genes related to muscle growth, patterning, and contractility, including the most extensively investigated GATA and NK families, are crucial in cardiovascular morphogenesis (15)(16)(17), and germline mutations in NKX2-5 (18-28), GATA4 (29-41), GATA5 (42)(43)(44)(45)(46), and GATA6 (47-55) have been associated with CHD. Nevertheless, the genetic basis underlying CHD remains to be clarified.…”

Section: Introductionmentioning

confidence: 99%

Somatic GATA5 mutations in sporadic tetralogy of Fallot

Huang

Xue

et al. 2014

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Abstract. Tetralogy of Fallot (TOF) is the most common form of cyanotic congenital heart disease, with high morbidity and mortality rates. Accumulating evidence has demonstrated that genetic defects play an important role in the pathogenesis of TOF. However, the molecular basis of TOF in the majority of patients remains to be determined. In the present study, sequence analysis of the coding exons and exon-intron boundaries of GATA5, a gene encoding a zinc finger-containing transcriptional factor crucial for cardiogenesis, was performed on genomic DNA isolated from resected cardiac tissue and matched blood samples of 85 unrelated patients who underwent surgical repair of TOF. Genotyping was performed on the cardiac tissue and matched blood samples from 63 unrelated patients who underwent cardiac valve replacement due to rheumatic heart disease as well as the blood samples obtained from 200 unrelated healthy individuals. The functional effect of the mutations was evaluated by using a luciferase reporter assay system. As a result, the novel heterozygous GATA5 mutations, p.D203E and p.Y208X, were found in the cardiac tissues of two TOF patients, respectively. There were no mutations in the cardiac tissues obtained from 63 patients with rheumatic heart disease nor in the blood samples obtained from the 348 subjects. Functional analysis revealed that the GATA5 mutants were consistently associated with significantly decreased transcriptional activity compared with their wild-type counterpart. Thus, results of this study showed an association of somatic GATA5 mutations with TOF, providing further insight into the underlying molecular mechanism of TOF.

“…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.