Atrial Natriuretic Peptide Frameshift Mutation in Familial Atrial Fibrillation

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 Informationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Huang

International Journal of Molecular Medicine

et al. 2012

“…While the structural heart diseases or systemic disorders, such as coronary artery disease, rheumatic heart disease, cardiomyopathy, congenital heart defects, pericarditis, congestive heart failure, hypertension, hyperthyroidism, and electrolyte imbalance, predispose to AF (4), AF also occurs in individuals without any known risk factors and growing evidence points to a genetic basis for the pathogenesis of AF (5)(6)(7)(8)(9)(10)(11)(12)(13). Furthermore, several chromosomal loci linked to AF have been mapped and AF-related mutations in multiple genes, including the connexin40 encoding cardiac gap junction membrane channel protein ·5, have been identified (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). However, AF is a genetically heterogeneous disorder and the molecular basis of AF remains unknown in the majority of cases (27).…”

Section: Introductionmentioning

confidence: 99%

Connexin40 nonsense mutation in familial atrial fibrillation

Yang

Zhang²,

Wang³

et al. 2010

Int J Mol Med

Abstract. Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia associated with substantial morbidity and mortality. Genetic variants play important roles in the pathogenesis of AF. However, AF is a genetically heterogeneous disorder, and the genetic determinants in most patients with AF remain to be identified. In this study, the entire coding region of the connexin40 gene, encoding the cardiac gap junction membrane channel protein ·5, was sequenced in 126 unrelated probands with familial AF. A novel heterozygous mutation, c.145C>T, in connexin40, was identified in a proband. The mutation was predicted to introduce a premature stop codon at amino acid position 49 (p.Q49X). This nonsense mutation was present in all the living relatives of the mutation carrier, co-segregating with AF in the family with a penetrance of 100%. However, it was absent in 200 ethnically matched unrelated control individuals. The findings suggest a pathogenic link between the compromised connexin40 function and familial AF, hence providing new insight into the molecular mechanisms involved in AF.

“…Genome-wide linkage analyses with polymorphic microsatellite markers mapped susceptibility loci for AF on human chromosomes 10q22, 6q14-16, 11p15.5, 5p13 and 5p15, of which AF-causing mutations in 2 genes, including KCNQ1 on chromosome 11p15.5 and NUP155 on chromosome 5p13, were identified and functionally characterized (19)(20)(21)(22)(23)(24). Genetic scan of candidate genes unveiled a long list of AF-associated genes, including KCNE2, KCNE3, KCNE5, KCNH2, KCNJ2, KCNJ8, KCNA5, SCN5A, NPPA, GATA4, GATA5 and GATA6 (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41). Nevertheless, AF is a genetically heterogeneous disorder and the genetic determinants for AF in the majority of patients remain to be identified (11).…”

Section: Introductionmentioning

confidence: 99%

Prevalence and spectrum of GJA5 mutations associated with lone atrial fibrillation

Shi

Yang

Molecular Medicine Reports

et al. 2012

Abstract. Atrial fibrillation (AF) is the most common form of cardiac arrhythmia observed in clinical practice and a major contributor to cardiovascular morbidity and mortality. Accumulating evidence indicates a substantial genetic basis for AF. However, AF is genetically heterogeneous and the hereditary components responsible for AF remain to be identified in the majority of patients. The cardiac gap junction protein α 5 (GJA5) is specifically expressed in atrial myocytes and is associated with the coordinated electrical activation of the atria, providing a rationale to screen GJA5 as a logical candidate gene for AF. A cohort of 310 unrelated patients with lone AF and their available relatives were included in this study. A group of 200 unrelated healthy individuals matched for age, gender and race were also included as controls. The entire coding region and splice sites of the GJA5 gene were initially sequenced in 310 unrelated AF patients. The relatives of mutation carriers and 200 controls were subsequently genotyped for the presence of identified mutations. As a result, 4 novel heterozygous GJA5 mutations, p.K107R, p.L223M, p.Q236H and p.I257L, were identified in 4 of 310 unrelated AF patients, respectively, with a prevalence of ~1.29%. Genetic analysis of the carriers' families showed that in each family the missense mutation was present in all the affected family members. Absent in the 400 reference alleles, these mutations altered the amino acids highly conserved among various species, with the exception of p.I257L. In conclusion, this study expands the spectrum of GJA5 mutations associated with AF and provides novel insights into the molecular basis of AF, suggesting potential implications for the improved, gene-specific rhythm control strategies.