Genetic screening of 104 patients with congenitally malformed hearts revealed a fresh mutation of <i>GATA4</i> in those with atrial septal defects

Hamanoue, Haruka; Rahayuningsih, Sri Endah; Hirahara, Yuya; Itoh, Junko; Yokoyama, Utako; Mizuguchi, Takeshi; Saitsu, Hirotomo; Miyake, Noriko; Hirahara, Fumiki; Matsumoto, Naomichi

doi:10.1017/s1047951109990813

Cited by 28 publications

(17 citation statements)

References 26 publications

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“…Nevertheless, the substantially varied prevalence of GATA4 mutations associated with congenital cardiovascular diseases was reported, which was roughly 0. (21)(22)(23)(24)(25)(26)(27)32,33,(36)(37)(38)(39). Similarly, a GATA4 mutation prevalence of nearly 0.5% (1/210) was observed in our VSD population, implying that the GATA4 mutations could be a minor cause of congenital VSD.…”

Section: Subject Information Phenotype Genotype ---------------------supporting

confidence: 65%

“…Hence, GATA4 has been one of the prime candidate genes in identifying the inheritable components for structural congenital cardiovascular defects. Presently, more than 40 mutations of the GATA4 gene have been identified in patients with a variety of congenital heart aberrations including VSDs, atrial septal defects, tetralogy of Fallot, endocardial cushion defects, patent ductus arteriosus, pulmonary stenosis, and hypoplastic right ventricle (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33). Nevertheless, the molecular mechanisms responsible for VSD in most patients remain to be elucidated (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33).…”

Section: Introductionmentioning

confidence: 99%

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A novel GATA4 mutation responsible for congenital ventricular septal defects

Wang

Fang²,

Liu³

et al. 2011

Int J Mol Med

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Abstract. Ventricular septal defect (VSD) is the most common type of cardiovascular developmental anomaly and is an important risk factor for the substantially increased morbidity and mortality in newborns. Aggregating evidence implicates genetic defects in the pathogenesis of congenital VSD. However, VSD is genetically heterogeneous and the genetic determinants for VSD in most patients remain to be identified. In this study, the whole coding region of the GATA4 gene, which encodes a zinc-finger transcription factor pivotal to cardiogenesis, was initially sequenced in 210 unrelated patients with VSD. The relatives of the index patient carrying the identified mutation and 200 unrelated ethnically-matched healthy individuals used as controls were subsequently genotyped. The functional effect of the mutant GATA4 was characterized in contrast to its wild-type counterpart using a luciferase reporter assay system. A novel heterozygous GATA4 mutation, p.G296R, was identified in a family with VSD inherited as an autosomal dominant trait. Absent in 200 control individuals, the mutation co-segregated with VSD in the family with 100% penetrance and was completely conserved evolutionarily across species. Functional analysis displayed that the p.G296R mutation of GATA4 was associated with a decreased transcriptional activity. The findings expand the spectrum of mutations in GATA4 linked to VSD and provide more insight into the molecular mechanism involved in VSD. The results of the present study imply the potential implications in the genetic diagnosis and gene-specific therapy of this common malformation in infancy.

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Section: Subject Information Phenotype Genotype ---------------------supporting

confidence: 65%

Section: Introductionmentioning

confidence: 99%

A novel GATA4 mutation responsible for congenital ventricular septal defects

Wang

Fang²,

Liu³

et al. 2011

Int J Mol Med

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“…Table 1 summarizes the many mutation screening studies that have been performed relevant to GATA4 gene [4]. So far, 24 different GATA4 germline mutations including 18 missense mutations [4,5,[7][8][9][10][11][12][13]37], 3 deletion mutations [4][5][6]9], and 3 insertion mutations [9,38] have been identified in different CHD patients. Among them, 6 mutations were associated with familial CHD [4][5][6][7][8][9].…”

Section: Resultsmentioning

confidence: 99%

Multiplex Ligation-Dependent Probe Amplification Analysis ofGATA4Gene Copy Number Variations in Patients with Isolated Congenital Heart Disease

et al. 2010

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Abstract. GATA4 mutations are found in patients with different isolated congenital heart defects (CHDs), mostly cardiac septal defects and tetralogy of Fallot. In addition, GATA4 is supposed to be the responsible gene for the CHDs in the chromosomal 8p23 deletion syndrome, which is recognized as a malformation syndrome with clinical symptoms of facial anomalies, microcephaly, mental retardation, and congenital heart defects. Thus far, no study has been carried out to investigate the role of GATA4 copy number variations (CNVs) in non-syndromic CHDs. To explore the possible occurrence of GATA4 gene CNVs in isolated CHDs, we analyzed by multiplex ligation-dependent probe amplification (MLPA) a cohort of 161 non-syndromic patients with cardiac anomalies previously associated with GATA4 gene mutations. The patients were mutation-negative for GATA4, NKX2.5, and FOG2 genes after screening with denaturing high performance liquid chromatography. MLPA analysis revealed that normalized MLPA signals were all found within the normal range values for all exons in all patients, excluding a major contribution of GATA4 gene CNVs in CHD pathogenesis.

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“…Currently, at least 14 germline mutations identified in the coding region of the GATA4 gene have been implicated with isolated or syndromic VSD, showing that although GATA4 mutations underlie a long list of cardiac developmental dysmorphias, one of the most common phenotypes ascribed to mutated GATA4 is VSD [3,4,6,9,14,23,24,26,31,33,36,41,47]. Nevertheless, the prevalence of GATA4 mutations varies significantly in different cohorts of individuals with congenital heart diseases, ranging from 0 to 12.50% [3,4,6,11,14,18,23,26,31,33,36,41,46,47].…”

Section: Discussionmentioning

confidence: 99%

A Novel GATA4 Loss-of-Function Mutation Associated With Congenital Ventricular Septal Defect

Yang

Wang

et al. 2011

Pediatr Cardiol

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Ventricular septal defect (VSD) is the most prevalent type of congenital heart disease and a major cause for the significantly increased morbidity and mortality among infants. Aggregating evidence indicates that genetic defects are involved in the pathogenesis of congenital VSD. Nevertheless, VSD is genetically heterogeneous, and the genetic determinants for VSD in the majority of patients remain to be identified. In this study, the entire coding region of GATA4, a gene encoding a zinc finger transcription factor essential for normal cardiac morphogenesis, was sequenced in 160 unrelated patients with VSD. The available relatives of the index patient harboring the identified mutation and 200 unrelated control individuals were subsequently genotyped. The disease-causing potential of a sequence alteration was evaluated by MutationTaster, and the functional effect of the mutation was characterized using a luciferase reporter assay system. As a result, a novel heterozygous GATA4 variation, p.R43W, was identified in a proband with VSD, that was absent in control subjects. Genetic analysis of the family members of the variation carrier showed that the substitution co-segregated with VSD. The p.R43W variant was predicted to be a pathogenic mutation, and the functional analysis demonstrated that the GATA4 R43W mutant protein resulted in significantly decreased transcriptional activity compared with its wild-type counterpart. The findings expand the mutational spectrum of GATA4 linked to VSD and provide more insight into the molecular mechanism of VSD.

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Genetic screening of 104 patients with congenitally malformed hearts revealed a fresh mutation of GATA4 in those with atrial septal defects

Cited by 28 publications

References 26 publications

A novel GATA4 mutation responsible for congenital ventricular septal defects

A novel GATA4 mutation responsible for congenital ventricular septal defects

Multiplex Ligation-Dependent Probe Amplification Analysis ofGATA4Gene Copy Number Variations in Patients with Isolated Congenital Heart Disease

A Novel GATA4 Loss-of-Function Mutation Associated With Congenital Ventricular Septal Defect

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