Novel NKX2–5 Mutations in Diseased Heart Tissues of Patients with Cardiac Malformations

Reamon-Buettner, Stella Marie; Hecker, Hartmut; Spanel‐Borowski, Katharina; Craatz, Steffen; Kuenzel, Eberhard; Borlak, Jürgen

doi:10.1016/s0002-9440(10)63770-4

Cited by 83 publications

(67 citation statements)

References 39 publications

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“…Somatic mutation leading to mosaicism is prevalent in cancer and is responsible for most leukemia, lymphomas and solid tumors (58). Somatic mutations have been identified in GATA4 and GATA6 as well as their transcriptionally cooperative partners, NXK2-5 and TBX5, in the cardiac tissue derived from a collection of hearts with CHD (59)(60)(61)(62)(63)(64)(65)(66)(67)(68). The expression and function of GATA5, a member of the GATA family, overlap at least partially with those of GATA4, GATA6, NKX2-5 and TBX5 during embryogenesis (12)(13)(14)(15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

Somatic GATA5 mutations in sporadic tetralogy of Fallot

Huang

Xue

et al. 2014

International Journal of Molecular Medicine

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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.

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Section: Introductionmentioning

confidence: 99%

Somatic GATA5 mutations in sporadic tetralogy of Fallot

Huang

Xue

et al. 2014

International Journal of Molecular Medicine

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“…Somatic mutations have been identified Somatic mutations in the GATA6 gene underlie sporadic tetralogy of Fallot in GATA4 and its molecular partners, NKX2-5 and TBX5, as well as the transcription factor HAND1 and HEY2 in cardiac tissue derived from hearts with CHD (40)(41)(42)(43)(44)(45)(46)(47)(48). GATA6 is another member of the GATA family, and its expression and function overlap at least partially with those of GATA4, NKX2-5 and TBX5 during cardiovascular genesis, which makes it logical to hypothesize that somatic GATA6 mutations are involved in the pathogenesis of TOF.…”

Section: Introductionmentioning

confidence: 99%

Somatic mutations in the GATA6 gene underlie sporadic tetralogy of Fallot

Huang

Xue

et al. 2012

International Journal of Molecular Medicine

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Abstract. Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease associated with significant morbidity and mortality in humans. However, the molecular etiology underlying TOF in most patients remains largely unknown. In the present study, sequence analysis of the GATA6 gene was performed from fresh-frozen cardiac tissues and matched blood samples of 52 unrelated patients who underwent surgical repair of TOF. The cardiac tissues and matched blood specimens from 46 patients who underwent cardiac valve replacement due to rheumatic heart disease and blood samples from 200 healthy individuals as controls were genotyped. The functional characteristics of the mutations were assessed using a luciferase reporter assay system. Based on the results, two novel heterozygous GATA6 mutations, p.G367X and p.G394C, were identified in the cardiac tissues of 2 TOF patients, respectively. No mutations were found in the cardiac tissues from 46 patients with rheumatic heart disease and in the blood samples from the 298 participants. Functional analysis demonstrated that the GATA6 mutants were consistently associated with significantly reduced transcriptional activation compared with their wildtype counterpart. This is the first report on the link of somatic GATA6 mutation to TOF, providing novel insight into the molecular mechanism involved in TOF.

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“…The authors considered them somatic and mosaic in origin. 12 The disease causative effect needs to be evaluated, as the changes could be artifacts owing to formalin fixation and paraffin embedding. Two mouse models have helped to understand the molecular basis of the cardiac defects observed in patients carrying CSX/NKX2-5 mutations.…”

Section: Introductionmentioning

confidence: 99%

A novel CSX/NKX2-5 mutation causes autosomal-dominant AV block: are atrial fibrillation and syncopes part of the phenotype?

et al. 2006

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The prevalence of congenital heart defects is approximately 1% of all live births. Identifying the genes responsible for cardiac malformation is the first step to understand pathogenesis. Heterozygous mutations in the CSX/NKX2-5 (NKX2E) gene have been identified to cause atrial septal defect (ASD) and/or atrioventricular (AV) conduction disturbance in some families. However, there is great variability in expressivity of the phenotype between the patients with a CSX/NKX2-5 mutation. We screened four sporadic patients and three index cases of families with ASD and/or conduction defects. In one of them, a CSX/NKX2-5 mutation was identified. This novel mutation (p.Tyr256X) was inherited in a three-generation family causing five individuals to have cardiac anomalies ranging from ASD to arrhythmias. Interestingly, all the observed AV conduction disturbances were at the nodal level, manifesting first as an AV block of the first degree and evolving toward a second-degree block. Atrial fibrillation, previously reported in three individuals with CSX/NKX2-5 mutations, was observed in three patients.

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Novel NKX2–5 Mutations in Diseased Heart Tissues of Patients with Cardiac Malformations

Cited by 83 publications

References 39 publications

Somatic GATA5 mutations in sporadic tetralogy of Fallot

Somatic GATA5 mutations in sporadic tetralogy of Fallot

Somatic mutations in the GATA6 gene underlie sporadic tetralogy of Fallot

A novel CSX/NKX2-5 mutation causes autosomal-dominant AV block: are atrial fibrillation and syncopes part of the phenotype?

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