Mapping a novel locus for familial atrial fibrillation on chromosome 10p11-q21

Huang

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: Alignment Of Multiple Gata5 Protein Sequences Across Speciesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Huang

et al. 2012

“…Increasing evidence demonstrates the familial aggregation of AF and an enhanced vulnerability to AF in the close relatives of patients with AF, suggesting that genetic defects may be involved in the pathogenesis of AF in a subset of patients (10)(11)(12)(13)(14)(15)(16). Genome-wide genetic linkage analysis with highly polymorphic microsatellite markers mapped susceptibility loci for AF on human chromosomes 10q22, 6q14-16, 11p15.5, 5p13, 10p11-q21 and 5p15, of which AF-causing mutations in two genes, KCNQ1 on chromosome 11p15.5 and NUP155 on chromosome 5p13, were identified and functionally characterized (17)(18)(19)(20)(21)(22)(23). In addition, genetic screening of candidate genes revealed an increasing number of AF associated mutations in genes encoding potassium channel subunits (KCNH2, KCNA5, KCNJ2, KCNJ8 and KCNE1-5), sodium channel subunits (SCN5A and SCN1B-3B), signaling peptide (NPPA), gap junctions (GJA1 and GJA5), and others .…”

Section: Introductionmentioning

confidence: 99%

A novel NKX2.5 loss-of-function mutation responsible for familial atrial fibrillation

Huang

Xue

et al. 2013

Abstract. Atrial fibrillation (AF) represents the most common form of sustained cardiac arrhythmia and accounts for substantial morbidity and mortality. Increasing evidence demonstrates that abnormal cardiovascular development is involved in the pathogenesis of AF. In this study, the coding exons and splice sites of the NKX2.5 gene, which encodes a homeodomain-containing transcription factor pivotal for normal cardiovascular morphogenesis, were sequenced in 110 unrelated index patients with familial AF. The available relatives of the mutation carrier and 200 unrelated ethnically-matched healthy individuals serving as controls were subsequently genotyped. The disease-causing potential of the identified NKX2.5 variation was predicted by MutationTaster. The functional characteristics of the mutant NKX2.5 protein were analyzed using a dual-luciferase reporter assay system. As a result, a novel heterozygous NKX2.5 mutation, p.F145S, was identified in a family with AF transmitted as an autosomal dominant trait, which co-segregated with AF in the family with complete penetrance. The detected substitution, which altered the amino acid completely conserved evolutionarily across species, was absent in 400 control chromosomes and was automatically predicted to be causative. Functional analysis demonstrated that the NKX2.5 mutant was associated with significantly decreased transcriptional activity compared with its wild-type counterpart. To the best of our knowledge, this is the first report on the association of the NKX2.5 lossof-function mutation with increased susceptibility to familial AF. The findings of the present study provide novel insights into the molecular mechanism underlying AF, suggesting the potential implications for the early prophylaxis and allelespecific therapy of AF.

“…A growing body of epidemiological research has demonstrated the familial aggregation of AF and the increased vulnerability to AF in the close relatives of patients with AF, strongly suggesting that genetic risk factors play a pivotal role in the pathogenesis of AF in a subset of patients (8)(9)(10)(11)(12)(13)(14). In previous studies, using genome-wide scanning with polymorphic microsatellite markers and linkage analysis, AF susceptibility loci were mapped on human chromosomes 10q22, 6q14-16, 11p15.5, 5p15, 10p11-q21 and 5p13, where AF-causative mutations in two genes, potassium voltage-gated channel, KQT-like subfamily, member 1 (KCNQ1) on chromosome 11p15.5 and nucleoporin 155 kDa (NUP155) on chromosome 5p13, were identified and functionally characterized (15)(16)(17)(18)(19)(20)(21). Direct analyses of candidate genes unveiled a high number of AF-related genes, including potassium voltage-gated channel, Isk-related family, member 2 (KCNE2), potassium voltage-gated channel, subfamily H (eag-related), member 2 (KCNH2), potassium inwardly-rectifying channel, subfamily J, member 2 (KCNJ2), potassium voltage-gated channel, shaker-related subfamily, member 5 (KCNA5), sodium channel, voltage-gated, type V, alpha subunit (SCN5A), sodium channel, voltage-gated, type IV, beta subunit (SCN4B), atrial natriuretic peptide (ANP), gap junction protein, alpha 5, 40 kDa (GJA5), GATA binding protein (GATA)4, GATA5, GATA6 and NK2 homeobox 5 (NKX2-5) .…”

Section: Introductionmentioning

confidence: 99%

A novel PITX2c loss-of-function mutation underlies lone atrial fibrillation

ZHOU

Zheng

Yang

et al. 2013

Abstract. Atrial fibrillation (AF) is the most common form of sustained cardiac arrhythmia responsible for substantial morbidity and significantly increased mortality rates. A growing body of evidence documents the important role of genetic defects in the pathogenesis of AF. However, AF is a heterogeneous disease and the genetic determinants for AF in an overwhelming majority of patients remain unknown. In the present study, a cohort of 100 unrelated patients with lone AF and a total of 200 unrelated, ethnically matched healthy individuals used as controls, were recruited. The whole coding exons and splice junctions of the pituitary homeobox 2c (PITX2c) gene, which encodes a paired-like homeobox transcription factor required for normal cardiovascular morphogenesis, were sequenced in the 100 patients and 200 control subjects. The causative potential of the identified mutation of PITX2c was predicted by MutationTaster and PolyPhen-2. The functional characteristics of the PITX2c mutation were assayed using a dual-luciferase reporter assay system. Based on the results, a novel heterozygous PITX2c mutation (p.T97A) was identified in a patient with AF. The missense mutation was absent in the 400 reference chromosomes and was automatically predicted to be disease-causing. Multiple alignments of PITX2c protein sequences across species revealed that the altered amino acid was completely conserved evolutionarily. Functional analysis demonstrated that the mutant PITX2c protein was associated with significantly decreased transcriptional activity when compared with its wild-type counterpart. The findings of the present study firstly link the PITX2c loss-of-function mutation to lone AF, and provide novel insight into the molecular mechanisms underlying AF, suggesting the potential implications for the early prophylaxis and allele-specific therapy of this common type of arrhythmia.