A novel stop mutation truncating critical regions of the cardiac transcription factor NKX2-5 in a large family with autosomaldominant inherited congenital heart disease

Pabst, Stefan; Wollnik, Bernd; Rohmann, Edyta; Hintz, Y.; Glänzer, K; Vetter, Hans; Nickenig, G; Grohé, Christian

doi:10.1007/s00392-007-0574-0

Cited by 36 publications

(13 citation statements)

References 12 publications

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“…On the contrary to de Divitiis et al [12], our study failed to identify the link between PWV and IMT or age at the operation. These observations suggest early determination of vascular changes in CoAo patients, the mechanism which is likely dependent on potential genetic or intrauterine factors [21, 40]. …”

Section: Discussionmentioning

confidence: 99%

Vascular remodeling in adults after coarctation repair: impact of descending aorta stenosis and age at surgery

et al. 2010

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BackgroundPatients after successful repair of coarctation of aorta (CoAo) are at risk of hypertension at rest and associated end-organ damage. The aim of the study was to assess arterial stiffness and function in adults after coarctation repair in relation to descending aorta (AoD) residual coarctation and patient’s age at operation.Methods85 patients after CoAo repair (53 males) aged 34.6 ± 10.3 years; median age at operation 0.9 ± 8.2 years. The control group—30 individuals (18 males) at mean age 33.6 ± 8.2 years. The following central parameters: augmentation pressure (AP) and augmentation index (AI) as well as peripheral vascular parameters: flow-mediated dilatation (FMD), nitroglycerin-mediated vasodilatation (NMD), intima-media thickness (IMT) and pulse wave velocity (PWV) were measured.Results47 CoAo-repaired patients were normotensive, and compared to control, they presented higher values of central parameters AP (7.3 ± 4.6 vs. 4.4 ± 3.6 mmHg; p = 0.002) and AI (18.6 ± 10.4 vs. 13.5 ± 4.3%; p = 0.03); as well as the increased PWV (6.8 ± 1.2 vs. 5.4 ± 0.9 m/s; p = 0.003), while IMT was comparable (0.53 ± 0.01 vs. 0.51 ± 0.01 mm; p = 0.06). The vasodilatation was impaired in the normotensive patients: FMD (4.8 ± 2.8 vs. 8.5 ± 2.3%; p = 0.00003) and NMD (11.3 ± 4.6 vs. 19.8 ± 7.2%; p = 0.00001). The comparison of recoarctation (46, 54%) to non-recoarctation (39, 46%) patients did not reveal any significant differences in resting systolic and diastolic pressures, as well as the values of AI and the peripheral vascular parameters; the value of AP was higher in the recoarctation patients (10.5 ± 6.9 vs. 7.5 ± 4.1; p = 0.02) and correlated positively with the gradient across AoD (r = 0.295, p = 0.01). There was no significant linear correlation between age at the time of surgery and any of peripheral arterial parameters.ConclusionsResidual stenosis in AoD does not affect the arterial vasodilatation nor stiffness in patients after CoAo repair. Early operation has no impact on peripheral vascular remodeling or central pressure which supports the claim that coarctation of the aorta is a systemic vascular disorder which leads to progressive vascular and end-organ damage despite early correction.

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Section: Discussionmentioning

confidence: 99%

Vascular remodeling in adults after coarctation repair: impact of descending aorta stenosis and age at surgery

et al. 2010

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“…In Nkx2-5-null mouse embryos, HCN4 was expressed in the entire embryonic heart tube, whereas connexin 40 expression was strongly reduced or absent and ectopic expression of pacemaker cells was observed throughout the heart tube (56). In humans, AF was reported as an isolated phenotype or a part of compound phenotype in patients harboring Nkx2-5 mutations (57)(58)(59). Therefore, as a transcriptionally cooperative partner of Nkx2-5, GATA4, when a loss-of-function mutation occurs, may contribute to formation of the pulmonary myocardium sleeve and shift of the pulmonary myocardium to a pacemaker-like phenotype by reducing the level of Nkx2-5, hence providing an atrial electrophysiological substrate facilitating AF.…”

Section: Discussionmentioning

confidence: 99%

Novel GATA4 mutations in lone atrial fibrillation

et al. 2011

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Abstract. Atrial fibrillation (AF) is the most frequent cardiac arrhythmia and is a major cause of morbidity and mortality. Previous studies have established genetic defects as a risk factor for AF in a minority of patients. However, AF is of substantial genetic heterogeneity and the molecular determinants for AF in a majority of cases remain unclear. In this study, the entire coding sequence and splice junctions of GATA4, which encodes a zinc-finger transcription factor essential for cardiogenesis, were sequenced in 160 unrelated patients with lone AF. A total of 200 unrelated ethnically matched healthy individuals were used as controls. The available relatives of the patient carrying an identified mutation were genotyped. The functional characteristics of the mutant GATA4 were analyzed using a luciferase reporter assay system. As a result, two novel heterozygous GATA4 mutations of p.G16C and p.H28D, were identified in 2 unrelated families with AF, respectively, which co-segregated with AF in each family with complete penetrance. Functional analysis demonstrated that the mutations of GATA4 were associated with a significantly decreased transcriptional activity. The findings expand the mutation spectrum of GATA4 linked to AF and provide novel insight into the molecular mechanism involved in the pathogenesis of AF.

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“…In NKX2-5-null mouse embryos, HCN4 was activated in the entire embryonic heart tube, whereas connexin40 expression was inhibited, and ectopic pacemaker cells were observed throughout the heart tube (63). In humans, AF was observed as an isolated phenotype or as a part of compound phenotypes in patients carrying NKX2-5 mutations (45,64,65). Therefore, as a transcriptionally cooperative partner of NKX2-5, GATA5, when a dominant negative mutation occurs, may contribute to the formation of the pulmonary myocardium sleeve and the shift of the pulmonary myocardium to a sinoatrial node-like phenotype by reducing NKX2-5, hence creating an atrial electrophysiological substrate liable to AF.…”

Section: Subject Informationmentioning

confidence: 99%

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

Wang

Huang

Wang

et al. 2012

International Journal of Molecular Medicine

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Abstract. Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is associated with significantly increased morbidity and mortality. Cumulative evidence highlights the importance of genetic defects in the pathogenesis of AF. However, AF is of remarkable heterogeneity and the genetic determinants of AF in a vast majority of patients remain illusive. In this study, the coding exons and splice junctions of the GATA5 gene, which encodes a zinc-finger transcription factor essential for normal cardiogenesis, were sequenced in 118 unrelated patients with lone AF. The available relatives of the index patient carrying an identified mutation and 200 unrelated ethnically-matched healthy individuals used as controls were genotyped. The functional effect of the mutant GATA5 was characterized in contrast to its wild-type counterpart using a luciferase reporter assay system. As a result, a novel heterozygous GATA5 mutation, p.W200G, was identified in a family with AF inherited as an autosomal dominant trait. The mutation was absent in 200 control individuals and the altered amino acid was completely conserved evolutionarily across species. Functional analysis showed that the mutation of GATA5 was associated with a significantly decreased transcriptional activity. These findings provide novel insight into the molecular mechanism involved in AF, suggesting potential implications for the early prophylaxis and genespecific therapy of AF.

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A novel stop mutation truncating critical regions of the cardiac transcription factor NKX2-5 in a large family with autosomaldominant inherited congenital heart disease

Cited by 36 publications

References 12 publications

Vascular remodeling in adults after coarctation repair: impact of descending aorta stenosis and age at surgery

Vascular remodeling in adults after coarctation repair: impact of descending aorta stenosis and age at surgery

Novel GATA4 mutations in lone atrial fibrillation

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

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