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

Huang

International Journal of Molecular Medicine

et al. 2012

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.

Section: Subject Informationsupporting

confidence: 88%

Section: Subject Informationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Huang

International Journal of Molecular Medicine

et al. 2012

“…Tbx20 interacts directly with Gata4, Gata5, Nkx2-5 (9), and Tbx5 (10) to regulate gene expression during embryogenesis. Mutations in genes encoding these factors in mice and humans consistently result in an array of structural and conduction cardiac defects of varying severity (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23).…”

Section: Introductionmentioning

confidence: 99%

Tbx20 regulates a genetic program essential to adult mouse cardiomyocyte function

Shen¹,

Aneas²,

Sakabe³

et al. 2011

J. Clin. Invest.

126

129

Human mutations in or variants of TBX20 are associated with congenital heart disease, cardiomyopathy, and arrhythmias. To investigate whether cardiac disease in patients with these conditions results from an embryonic or ongoing requirement for Tbx20 in myocardium, we ablated Tbx20 specifically in adult cardiomyocytes in mice. This ablation resulted in the onset of severe cardiomyopathy accompanied by arrhythmias, with death ensuing within 1 to 2 weeks of Tbx20 ablation. Accounting for this dramatic phenotype, we identified molecular signatures that posit Tbx20 as a central integrator of a genetic program that maintains cardiomyocyte function in the adult heart. Expression of a number of genes encoding critical transcription factors, ion channels, and cytoskeletal/myofibrillar proteins was downregulated consequent to loss of Tbx20. Genome-wide ChIP analysis of Tbx20-binding regions in the adult heart revealed that many of these genes were direct downstream targets of Tbx20 and uncovered a previously undescribed DNA-binding site for Tbx20. Bioinformatics and in vivo functional analyses revealed a cohort of transcription factors that, working with Tbx20, integrated multiple environmental signals to maintain ion channel gene expression in the adult heart. Our data provide insight into the mechanisms by which mutations in TBX20 cause adult heart disease in humans.

“…In agreement with observations in patients, mouse genetics has revealed the complexity of the role of Nkx2-5. [16][17][18][19] Germline deletion of Nkx2-5 gene results in cardiac lethality at the early stages with defects in the myocardial wall thickening, trabeculation, and endocardial cushion formation, suggesting a pro-mitotic role of Nkx2-5. 4,12,13 Recent studies have shown that Nkx2-5 also plays a critical role at chamber ballooning stages.…”

mentioning

confidence: 99%

Nkx2-5 Suppresses the Proliferation of Atrial Myocytes and Conduction System

Nakashima

Yanez

Touma

et al. 2014

Circulation Research

A bout 0.9% of human neonates are born with congenital heart disease (CHD). CHD can arise from genetic and epigenetic abnormalities that affect the tight control of specification, proliferation, and migration of cardiac progenitors/myocytes.1,2 During cardiogenesis, cardiac progenitors/myocytes proliferate in two waves: primitive heart tube shows highest proliferative activity at arterial and venous poles where latemigrating second heart field progenitors are recruited. 3,4 Then, after the completion of looping, the working myocytes reinitiate mitotic activity, resulting in the ballooning of chambers at late gestational stages. 3,5 Non-ballooning regions, mainly mediastinal myocardium, 6,7 are distinct from appendage myocardium in their morphology, expression profile, 8 and ionic currents. Nkx2-5 is a cardiac homeobox transcription factor that is expressed in a broad range of cardiac sublineages, from the early committed cardiac progenitors through the adult cardiomyocytes, and plays a pivotal role in the regulation of cardiac, vascular, and hematopoietic lineages. 4,[10][11][12][13][14][15] Human heterozygous mutations of NKX2-5 are associated with a spectrum of CHDs including septal defects, conotruncal malformations, hypoplastic left heart, and atrioventricular (AV) conduction block. In agreement with observations in patients, mouse genetics has revealed the complexity of the role of Nkx2-5. [16][17][18][19] Germline deletion of Nkx2-5 gene results in cardiac lethality at the early stages with defects in the myocardial wall thickening, trabeculation, and endocardial cushion formation, suggesting a pro-mitotic role of Nkx2-5. 4,12,13 Recent studies have shown that Nkx2-5 also plays a critical role at chamber ballooning stages. 3,5 Mutant mouse models with genetic deficiency or dysfunction of Nkx2-5 after midgestational stages lead to atrial septal defect (ASD) and conduction defects. [20][21][22][23][24] Despite common phenotypes, however, these studies show partially inconsistent results as to cardiomyocyte growth. Although the temporary controlled global deletion of Nkx2-5 after midgestational stage results in thin hypomorphic ventricle, 24 ventricular-specific deletion of Nkx2-5 shows hypertrophic ventricle with hypertrabeculation. 22 These apparently conflicting results can be, in part, due to the differential regulation of physiological cardiac growth in spatiotemporarily Rationale: Tight control of cardiomyocyte proliferation is essential for the formation of four-chambered heart.Although human mutation of NKX2-5 is linked to septal defects and atrioventricular conduction abnormalities, early lethality and hemodynamic alteration in the mutant models have caused controversy as to whether Nkx2-5 regulates cardiomyocyte proliferation. diverse cardiac subpopulation. In addition, the secondary effect by altered pump function in Nkx2-5 mutants may be another factor that complicates the interpretation of the phenotypes of mouse models mentioned above. In fact, hemodynamics by itself is known to be an indepen...