Abstract 2922: KCNQ1 Gain-of-function Mutation Associated With Familial Atrial Fibrillation

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Dawood Darbar ◽  
Robert Abraham ◽  
Gayle Kucera ◽  
Tanya Stubblefield ◽  
Tao Yang ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Action Potentials ◽  
Markov Models ◽  
Type I ◽  
Gain Of Function ◽  
Qt Intervals ◽  
Caucasian Family ◽  
Affected Family Member ◽  
Familial Atrial Fibrillation

Background : Family history is a risk factor for atrial fibrillation (AF). We report here a 3-generation Caucasian family with familial AF and a highly dysfunctional mutation in KCNQ1 . Methods and Results: In the proband, there was a 9-bp duplication resulting in insertion of the amino acids IAP (IAP54 –56) in the N-terminus of the protein. The kindred included 4 other family members with AF or palpitations. Each affected family member presented with early onset paroxysmal lone AF and no QT prolongation. This variant has previously been reported in presumed healthy African-American individuals (minor allele frequency 1.3%), but has not been studied in vitro . In transfected CHO cells, coexpression of IAP54 –56 with KCNE1 generated currents that were much larger and activated much earlier that wild-type I Ks ( Figure ); e.g. at +20 mV, peak current was 75±8 [IAP54 –56] vs 25±5 [wt] pA/pF after 5-sec pulses (n=7 each, P<0.001). Computational simulations of human atrial action potential (AP) that incorporated Markov models of wt or IAP54 –56-I Ks were performed. At a cycle length of 400ms, accelerated activation of IAP54 –56-I Ks resulted in open state accumulation and increased maximum I Ks amplitude ~40-fold (351 vs 9 pA/pF), resulting in ~6-fold AP duration shortening (44 vs 259 ms). Conclusions: We have identified a KCNQ1 indel in a moderate sized Caucasian kindred with familial AF and normal QT intervals. This variant results in an I Ks gain-of-function and the resulting shortening of atrial action potentials may predispose to AF. This variant has been reported in 1.3% of African-Americans, suggesting it may be a common risk allele in some populations.

Abstract 1523: A Novel SCN5A Gain-of-Function Mutation M1875T Associated with Familial Atrial Fibrillation

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Takeru Makiyama ◽  
Masaharu Akao ◽  
Satoshi Shizuta ◽  
Takahiro Doi ◽  
Kei Nishiyama ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Mutational Analysis ◽  
Gain Of Function ◽  
Japanese Family ◽  
Function Type ◽  
Whole Cell Patch Clamp ◽  
Steady State Inactivation ◽  
Familial Atrial Fibrillation ◽  
The Right ◽  
Inherited Arrhythmias

Background: Mutations in the cardiac sodium (Na + ) channel gene, SCN5A , have been associated with a variety of inherited arrhythmias, but the gain-of-function type modulation in SCN5A is associated with only one phenotype, long-QT syndrome type3 (LQTS3). Methods and Results: We studied a Japanese family with autosomal dominant hereditary atrial fibrillation (AF), multiple members of which showed onset of AF or frequent premature atrial contractions at a young age. The 31-year-old proband received radio-frequency catheter ablation, during which time numerous ectopic firings and increased excitability throughout the right atrium were documented. Mutational analysis identified a novel missense mutation, M1875T, in SCN5A . Further investigations revealed the aggregation of this mutation in all of the affected individuals (Figure A ). Functional assays of the M1875T Na + channels using whole-cell patch-clamp demonstrated a distinct gain-of-function type modulation; a pronounced depolarized shift (+16.4 mV) in V 1/2 of the voltage dependence of steady-state inactivation (Figure B ), and no late Na + current which is a defining mechanism of LQTS3. These biophysical features of the mutant channels are potentially associated with increased atrial excitability and normal QT interval in all of the affected individuals. Conclusions: We identified a novel SCN5A mutation associated with familial AF. The mutant channels displayed a gain-of-function type modulation of cardiac Na + channels, which is a novel mechanism predisposing increased atrial excitability and familial AF. This is a new phenotype resulting from the SCN5A gain-of-function mutations and is distinct from LQTS3.

Abstract 357: Novel Gain of Function SCN5A Mutation Causes Familial Atrial Fibrillation

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Julie Rutberg ◽  
Hai Huang ◽  
Robert Lemery ◽  
Anthony Tang ◽  
David Birnie ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Sodium Channel ◽  
Paroxysmal Atrial Fibrillation ◽  
Gain Of Function ◽  
Mutant Channel ◽  
Functional Studies ◽  
Channel Gene ◽  
Sodium Channel Gene ◽  
Familial Atrial Fibrillation ◽  
Scn5a Mutation

Background : Few genetic etiologies are known for familial or sporadic cases of atrial fibrillation, which is the most common arrhythmia in older adults. We report a mother and son, both with atrial fibrillation, who were found to have a novel mutation in the sodium channel gene, SCN5A. Case History: The proband, a 50 year old male, first developed paroxysmal atrial fibrillation following orthopedic surgery. At age 57, he presented with increasing fatigue and shortness of breath and was found to have chronic atrial fibrillaion. Cardiac testing found no evidence of ischemia, normal left ventricular function and mild left atrial dilation. His mother had paroxysmal atrial fibrillation, diagnosed at age 63, and a history of well-controlled hypertension and palpitations. Her atrial fibrillation was initially controlled by sotalol, but worsening symptoms led to a change to amiodarone at age 83. Her echo showed mild biatrial enlargement. ECGs for the proband and his mother have never demonstrated conduction system disease, long QT, or a Brugada pattern. Methods and Results: Genomic DNA isolated from blood lymphocytes was screened using direct sequencing techniques. Genes previously reported to be associated with atrial fibrillation, KCNA5, GJA5 and KCNQ1, were screened and no mutations were found. In the sodium channel gene, SCN5A, a novel missense mutation was identified (c. 1493K>R) in both the proband and his mother, but not in an unaffected sibling or in the proband’s 2 asymptomatic offspring. The mutation is in a highly conserved lysine residue in the voltage-gated sodium channel gene family. Functional studies recorded macroscopic sodium currents from tsA201 cells expressing both the wild-type (Nav1.5/WT) and mutant channel (Nav1.5/K1493R). The mutant channel exhibited fast activation and inactivation kinetics and an increase in current density. No effect on steady-state activation and inactivation were observed, however, current deactivation was faster in mutant Nav1.5/K1493R as compared to the WT channels. Conclusions: This is the first report of an inherited SCN5A mutation in familial atrial fibrillation. Functional studies suggest a ’gain-of-function’ effect of the identified Nav1.5/K1493R mutation.

scholarly journals A Novel PITX2c Gain-of-Function Mutation, p.Met207Val, in Patients With Familial Atrial Fibrillation

2019 ◽  
Vol 123 (5) ◽  
pp. 787-793 ◽  
Author(s):  
Asma Mechakra ◽  
Tim Footz ◽  
Michael Walter ◽  
Amelia Aránega ◽  
Francisco Hernández-Torres ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Gain Of Function ◽  
Familial Atrial Fibrillation

scholarly journals Identification of a KCNE2 Gain-of-Function Mutation in Patients with Familial Atrial Fibrillation

2004 ◽  
Vol 75 (5) ◽  
pp. 899-905 ◽  
Author(s):  
Yiqing Yang ◽  
Min Xia ◽  
Qingfeng Jin ◽  
Saïd Bendahhou ◽  
Jingyi Shi ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Gain Of Function ◽  
Familial Atrial Fibrillation

A Kir2.1 gain-of-function mutation underlies familial atrial fibrillation

2005 ◽  
Vol 332 (4) ◽  
pp. 1012-1019 ◽  
Author(s):  
Min Xia ◽  
Qingfeng Jin ◽  
Saïd Bendahhou ◽  
Yusong He ◽  
Marie-Madeleine Larroque ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Gain Of Function ◽  
Familial Atrial Fibrillation

Abstract 18012: Modeling of a Rare SCN10A Variant (A1886V) Linked with Early-Onset Atrial Fibrillation Shortens Atrial Action Potential Duration

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Robert L Abraham ◽  
Eleonora Savio-Galimberti ◽  
Tao Yang ◽  
Dan M Roden ◽  
Dawood Darbar
Keyword(s):  
Atrial Fibrillation ◽  
Action Potential ◽  
Early Onset ◽  
Action Potential Duration ◽  
Markov Models ◽  
Phase 1 ◽  
Electrophysiological Studies ◽  
Synonymous Variant ◽  
Onset Atrial Fibrillation

Introduction: SCN10A encodes the tetrodotoxin-resistant sodium channel isoform Nav1.8, which is variably expressed in neuronal tissue and heart and has been associated with atrial fibrillation (AF). We resequenced the SCN10A gene in 274 early-onset AF probands and identified a rare non-synonymous variant (A1886V) that co-segregated with AF in a kindred. In-vitro electrophysiological studies revealed that this variant displayed a “gain-of-function” phenotype with increased peak (INa-peak) and late (INa-L) sodium currents. Hypothesis: Here, we hypothesized that the increased peak and late INa associated with A1886V variant might modulate atrial action potential duration (APD) and thus increase susceptibility to AF. Methods: We used 2 Clancy-Rudy INa Markov models modified to fit wild-type (WT) and A1886V variant. Modeled currents were incorporated into the Courtemanche-Ramirez-Nattel model of human atrial AP. The overall SCN10A/Nav1.8 contribution to the total INa was simulated in the 5-50% range of WT-SCN5A/Nav1.5 current, and for each overall SCN10A magnitude, the contribution of A1886V compared to WT was simulated in the 0-to-100% range. Cycle-length used was 1000 ms (frequency 1 Hz). Results: While the precise magnitude of SCN10A atrial expression (WT and A1886V) has not yet been determined, simulation of a range of contributions of each component to atrial AP demonstrated incremental morphology changes with removal of the “spike and dome” and triangularization of AP associated with progressive shortening of APD90 (301 ms at 0% SCN10A contribution; 281 ms at 10% SCN10A [100% WT, 0% A1886V]; 261 ms at 10% SCN10A [0% WT, 100% A1886V]) (Table). Conclusion: Computational modeling of A1886V-SCN10A rare variant linked with familial AF surprisingly shortened atrial APD by removal of phase 1 “spike and dome” and augmentation of atrial AP “triangularization”, providing a potential mechanism for increased AF susceptibility.

scholarly journals A Novel SCN5A Gain-of-Function Mutation M1875T Associated With Familial Atrial Fibrillation

2008 ◽  
Vol 52 (16) ◽  
pp. 1326-1334 ◽  
Author(s):  
Takeru Makiyama ◽  
Masaharu Akao ◽  
Satoshi Shizuta ◽  
Takahiro Doi ◽  
Kei Nishiyama ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Gain Of Function ◽  
Familial Atrial Fibrillation

Comprehensive In Vitro and In Vivo Characterization of Loss and Gain-of-Function Von Willebrand Factor Collagen Binding Variants Using a Mouse Model System,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3266-3266
Author(s):  
Yasuaki Shida ◽  
Christine Brown ◽  
Jeff Mewburn ◽  
Kate Sponagle ◽  
Ozge Danisment ◽  
...  
Keyword(s):  
Deletion Mutant ◽  
Platelet Adhesion ◽  
Collagen Type ◽  
Collagen Type I ◽  
Type I ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Collagen Binding

Abstract Abstract 3266 Von Willebrand Factor (VWF) is a large multimeric glycoprotein that mediates platelet adhesion to the damaged blood vessel wall and subsequent platelet aggregation at the site of injury. Rare mutations in the VWF A3 domain, that disrupt collagen binding, have been found in patients with a mild bleeding phenotype. However, the analysis of these aberrant VWF-collagen interactions has been relatively limited. Thus, in this study, we have developed mouse models of collagen binding mutants and analyzed the function of the A3 and A1 domains using comprehensive in vitro and in vivo approaches. All of the collagen binding variant AAs are conserved in mice. 6 loss-of-function (S1731T, W1745C, S1783A, H1786D, A1 deletion, A3 deletion) and 1 gain-of-function (L1757A) variant was generated in the context of the mouse VWF cDNA. The 4 loss-of-function missense mutants have all been described in patients with mild bleeding phenotypes. The recombinant mouse VWFs (rmVWF) were synthesized in HEK293T cells and analyzed for type I and III collagen binding in both a static assay (CBA) and a flow-based assay at 2,500s−1 in which VWF is bound to collagen on a surface, and labeled platelet adhesion is quantified. The multimer profile of all the rmVWFs was normal. The expression level of the rmVWF derived from HEK293T cells was quantified. W1745C and the A3 deletion showed significantly lower levels of expression and the A1 deletion mutant showed strong intracellular retention. In the static collagen binding assay, S1731T showed almost normal binding to collagen type I and a 50% reduction in binding to collagen type III. The other 3 missense variants, W1745C, S1783A and H1786D, showed reduced binding to both collagens I and III, and the A3 deletion mutant showed absent binding. In the in vitro flow assay, the sensitivity to detect defects in collagen binding was superior to the static assay, although the patterns of binding defects were similar. W1745C showed similar low levels of platelet adhesion to both types of collagen, while S1783A and H1786D showed a lack of platelet binding on the collagen III surface similar to the A3 deletion mutant, and a reduced binding to collagen type I similar to W1745C. The gain-of-function mutant showed consistent enhanced collagen binding and platelet adhesion in the static and flow assays, respectively. In vivo studies delivered the mVWF cDNAs with a strong liver specific promoter by hydrodynamic injection. At 7 days post-delivery, the VWF:Ag levels in the WT and collagen binding variant mice were similar, apart from the W1745C mutant, that showed 14.6% levels compared to WT. Platelet counts and multimer patterns were normal with the collagen binding variants. In vivo intravital microscopy studies were performed using the cremaster arteriolar model when VWF levels were in a physiological range. Thrombosis was induced by 10%FeCl3 applied for 3 mins. Platelets were labeled in vivo by Rhodamine 6G and the thrombus development was analyzed by spinning disc confocal microscopy. Loss-of-function mutants showed transient platelet adhesion at the site of injury, however the adhesion was unstable and vessel occlusion was not observed. Using three complementary experimental systems we have been able to confirm the collagen binding defects in this group of variant VWFs. There is a differential sensitivity to the two forms of collagen and of the three experimental systems. The A3 deletion mutant consistently resulted in the most severe phenotype while the missense mutants showed variable degrees of functional deficit. Disclosures: No relevant conflicts of interest to declare.

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