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SCN5A Mutations

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https://www.readbyqxmd.com/read/29214556/influence-of-genetic-modifiers-on-sudden-cardiac-death-cases
#1
Tina Jenewein, Thomas Neumann, Damir Erkapic, Malte Kuniss, Marcel A Verhoff, Gerhard Thiel, Silke Kauferstein
Sequence variants in the ion channel genes KCNH2 and SCN5A may cause the cardiac disorder long QT syndrome (LQTS). This disorder is associated with incomplete penetrance and variable expression in KCNH2- or SCN5A-mutation carriers. Common genetic variants, if associated with a mutation, may affect the severity of this cardiac disorder. This study identified rare mutations in the cardiac ion channel genes KCNH2 and SCN5A in a SCD case, as well as in a LQTS-affected family with a history of SCD. Moreover, common variants were found to occur together within the same genes...
December 6, 2017: International Journal of Legal Medicine
https://www.readbyqxmd.com/read/29202755/h558r-a-common-scn5a-polymorphism-modifies-the-clinical-phenotype-of-brugada-syndrome-by-modulating-dna-methylation-of-scn5a-promoters
#2
Hiroya Matsumura, Yukiko Nakano, Hidenori Ochi, Yuko Onohara, Akinori Sairaku, Takehito Tokuyama, Shunsuke Tomomori, Chikaaki Motoda, Michitaka Amioka, Naoya Hironobe, Masaaki Toshishige, Shinya Takahashi, Katsuhiko Imai, Taijiro Sueda, Kazuaki Chayama, Yasuki Kihara
BACKGROUND: A common SCN5A polymorphism H558R (c.1673 A > G, rs1805124) improves sodium channel activity in mutated channels and known to be a genetic modifier of Brugada syndrome patients (BrS). We investigated clinical manifestations and underlying mechanisms of H558R in BrS. METHODS AND RESULTS: We genotyped H558R in 100 BrS (mean age 45 ± 14 years; 91 men) and 1875 controls (mean age 54 ± 18 years; 1546 men). We compared clinical parameters in BrS with and without H558R (H558R+ vs...
December 4, 2017: Journal of Biomedical Science
https://www.readbyqxmd.com/read/29172153/ajmaline-blocks-ina-and-ikr-without-eliciting-differences-between-brugada-syndrome-patient-and-control-human-pluripotent-stem-cell-derived-cardiac-clusters
#3
Duncan C Miller, Stephen C Harmer, Ariel Poliandri, Muriel Nobles, Elizabeth C Edwards, James S Ware, Tyson V Sharp, Tristan R McKay, Leo Dunkel, Pier D Lambiase, Andrew Tinker
The class Ia anti-arrhythmic drug ajmaline is used clinically to unmask latent type I ECG in Brugada syndrome (BrS) patients, although its mode of action is poorly characterised. Our aims were to identify ajmaline's mode of action in human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs), and establish a simple BrS hiPSC platform to test whether differences in ajmaline response could be determined between BrS patients and controls. Control hiPSCs were differentiated into spontaneously contracting cardiac clusters...
November 7, 2017: Stem Cell Research
https://www.readbyqxmd.com/read/29167113/irritable-bowel-syndrome-ibs-patients-have-scn5a-channelopathies-that-lead-to-decreased-nav1-5-current-and-mechanosensitivity
#4
Peter R Strege, Amelia Mazzone, Cheryl E Bernard, Leila Neshatian, Simon J Gibbons, Yuri A Saito, David J Tester, Melissa L Calvert, Emeran A Mayer, Lin Chang, Michael J Ackerman, Arthur Beyder, Gianrico Farrugia
The SCN5A-encoded voltage-gated mechanosensitive sodium (Na(+)) channel NaV1.5 is expressed in human GI smooth muscle cells and interstitial cells of Cajal. NaV1.5 contributes to smooth muscle electrical slow waves and mechanical sensitivity. In predominately Caucasian IBS patient cohorts, 2-3% have SCN5A missense mutations which alter NaV1.5 function and may contribute to IBS pathophysiology. In this study examined a racially and ethnically diverse cohort of IBS patients for SCN5A missense mutations, and compared them to IBS negative controls, and determined the resulting NaV1...
November 22, 2017: American Journal of Physiology. Gastrointestinal and Liver Physiology
https://www.readbyqxmd.com/read/29132927/whole-exome-sequencing-identified-a-pathogenic-mutation-in-ryr2-in-a-chinese-family-with-unexplained-sudden-death
#5
Yubi Lin, Siqi He, Zili Liao, Ruiling Feng, Ruilin Liu, Yongzheng Peng, Nan Yu, Hang Qi, Jia Chen, Zifeng Huang, Heping Lei, Yang Liu, Fang Rao, Chunyu Deng, Yumei Xue, Guolin Zhang, Bin Zhang, Hua Yao, Shulin Wu
OBJECTIVE: This study aimed to identify the pathogenic mutation in a Chinese family with unexplained sudden death (USD) or occasional syncope. MATERIALS AND METHODS: Whole exome sequencing and target capture sequencing were respectively conducted for two related patients. The genetic data was screened using the 1000 genomes project and SNP database (PubMed), and the identified mutations were assessed for predicted pathogenicity using the SIFT and Polyphen-2 algorithms...
October 10, 2017: Journal of Electrocardiology
https://www.readbyqxmd.com/read/29121719/implantable-cardioverter-defibrillator-therapy-in-repaired-tetralogy-of-fallot-after-pulmonary-valve-replacement-implications-for-the-mechanism-of-ventricular-arrhythmia
#6
Shuenn-Nan Chiu, Shu-Chien Huang, Jou-Kou Wang, Chun-Wei Lu, Ling-Yin Chang, Ming-Tai Lin, Chun-An Chen, Yih-Sharng Chen, Mei-Hwan Wu
BACKGROUND: Ventricular tachycardia (VT), which is related to haemodynamic and electrophysiological alterations, is an important complication in repaired tetralogy of Fallot (rTOF) patients. We defined the role of implantable cardioverter defibrillator (ICD) therapy after pulmonary valve replacement (PVR) and the implications of coexisting long QT gene mutations/polymorphisms. METHODS: From 2003 to 2016, rTOF patients with VT who received ICD implantation were enrolled...
December 15, 2017: International Journal of Cardiology
https://www.readbyqxmd.com/read/29101013/the-congenital-long-qt-syndrome-type-3-an-update
#7
REVIEW
Andrés Ricardo Pérez-Riera, Raimundo Barbosa-Barros, Rodrigo Daminello Raimundo, Marianne Penachini da Costa de Rezende Barbosa, Isabel Cristina Esposito Sorpreso, Luiz Carlos de Abreu
Congenital long QT syndrome type 3 (LQT3) is the third in frequency compared to the 15 forms known currently of congenital long QT syndrome (LQTS). Cardiac events are less frequent in LQT3 when compared with LQT1 and LQT2, but more likely to be lethal; the likelihood of dying during a cardiac event is 20% in families with an LQT3 mutation and 4% with either an LQT1 or an LQT2 mutation. LQT3 is consequence of mutation of gene SCN5A which codes for the Nav1.5 Na(+) channel α-subunit and electrocardiographically characterized by a tendency to bradycardia related to age, prolonged QT/QTc interval (mean QTc value 478 ± 52 ms), accentuated QT dispersion consequence of prolonged ST segment, late onset of T wave and frequent prominent U wave because of longer repolarization of the M cell across left ventricular wall...
October 31, 2017: Indian Pacing and Electrophysiology Journal
https://www.readbyqxmd.com/read/29077258/whole-exome-sequencing-identifies-a-novel-mutation-of-gpd1l-r189x-associated-with-familial-conduction-disease-and-sudden-death
#8
Hao Huang, Ya-Qin Chen, Liang-Liang Fan, Shuai Guo, Jing-Jing Li, Jie-Yuan Jin, Rong Xiang
Cardiac conduction disease (CCD) is a serious disorder and the leading cause of mortality worldwide. It is characterized by arrhythmia, syncope or even sudden cardiac death caused by the dysfunction of cardiac voltage-gated channel. Previous study has demonstrated that mutations in genes encoding voltage-gated channel and related proteins were the crucial genetic lesion of CCD. In this study, we employed whole-exome sequencing to explore the potential causative genes in a Chinese family with ventricular tachycardia and syncope...
October 27, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/29062695/inaccurate-diagnosis-of-brugada-syndrome-in-a-healthy-woman-based-on-scn5a-mutation-classification
#9
Simrit K Warring, Heather N Anderson, J Martijn Bos, Michael J Ackerman
No abstract text is available yet for this article.
October 2017: HeartRhythm Case Reports
https://www.readbyqxmd.com/read/29032483/regulation-of-cardiac-voltage-gated-sodium-channel-by-kinases-roles-of-protein-kinases-a-and-c
#10
Ademuyiwa S Aromolaran, Mohamed Chahine, Mohamed Boutjdir
In the heart, voltage-gated sodium (Nav) channel (Nav1.5) is defined by its pore-forming α-subunit and its auxiliary β-subunits, both of which are important for its critical contribution to the initiation and maintenance of the cardiac action potential (AP) that underlie normal heart rhythm. The physiological relevance of Nav1.5 is further marked by the fact that inherited or congenital mutations in Nav1.5 channel gene SCN5A lead to altered functional expression (including expression, trafficking, and current density), and are generally manifested in the form of distinct cardiac arrhythmic events, epilepsy, neuropathic pain, migraine, and neuromuscular disorders...
October 15, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/29024690/sodium-channel-current-loss-of-function-in-induced-pluripotent-stem-cell-derived-cardiomyocytes-from-a-brugada-syndrome-patient
#11
Elisabet Selga, Franziska Sendfeld, Rebecca Martinez-Moreno, Claire N Medine, Olga Tura-Ceide, Sir Ian Wilmut, Guillermo J Pérez, Fabiana S Scornik, Ramon Brugada, Nicholas L Mills
Brugada syndrome predisposes to sudden death due to disruption of normal cardiac ion channel function, yet our understanding of the underlying cellular mechanisms is incomplete. Commonly used heterologous expression models lack many characteristics of native cardiomyocytes and, in particular, the individual genetic background of a patient. Patient-specific induced pluripotent stem (iPS) cell-derived cardiomyocytes (iPS-CM) may uncover cellular phenotypical characteristics not observed in heterologous models...
October 9, 2017: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/28988457/re-evaluating-pathogenicity-of-variants-associated-with-the-long-qt-syndrome
#12
Jonathan R Kaltman, Frank Evans, Yi-Ping Fu
INTRODUCTION: Genetic testing for congenital long-QT syndrome (LQTS) has become common. Recent studies have shown that some variants labelled as pathogenic might be misclassified due to sparse case reports and relatively common allele frequencies in the general population. This study aims to evaluate the presence of LQTS-associated variants in the Genome Aggregation Database (gnomAD) population, and assess the functional impact of these variants. METHODS AND RESULTS: Variants associated with LQTS from the Human Gene Mutation Database were extracted and matched to the gnomAD to evaluate population-based allele frequencies (AF)...
October 8, 2017: Journal of Cardiovascular Electrophysiology
https://www.readbyqxmd.com/read/28894151/the-effects-of-ageing-and-adrenergic-challenge-on-electrocardiographic-phenotypes-in-a-murine-model-of-long-qt-syndrome-type-3
#13
Karan R Chadda, Shiraz Ahmad, Haseeb Valli, Ingrid den Uijl, Ali Bak Al-Hadithi, Samantha C Salvage, Andrew A Grace, Christopher L-H Huang, Kamalan Jeevaratnam
Long QT Syndrome 3 (LQTS3) arises from gain-of-function Nav1.5 mutations, prolonging action potential repolarisation and electrocardiographic (ECG) QT interval, associated with increased age-dependent risk for major arrhythmic events, and paradoxical responses to β-adrenergic agents. We investigated for independent and interacting effects of age and Scn5a+/ΔKPQ genotype in anaesthetised mice modelling LQTS3 on ECG phenotypes before and following β-agonist challenge, and upon fibrotic change. Prolonged ventricular recovery was independently associated with Scn5a+/ΔKPQ and age...
September 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28878402/genetic-mechanisms-contribute-to-the-development-of-heart-failure-in-patients-with-atrioventricular-block-and-right-ventricular-apical-pacing
#14
Nana Liu, Min Zheng, Shijie Li, Hui Bai, Zhouying Liu, Cui Hong Hou, Shu Zhang, Jielin Pu
Right ventricular apical (RVA) pacing can lead to progressive left ventricular dysfunction and heart failure (HF), even in patients with normal cardiac structure and function. Our study conducted candidate gene screening and lentivirus transfected neonatal rat cardiomyocytes (NRCMs) to explore the genetic and pathogenic mechanisms of RVA pacing induced cardiomyopathy in third degree atrioventricular block (III AVB) patients. We followed 887 III AVB patients with baseline normal cardiac function and RVA pacing...
September 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28837624/rare-variants-in-genes-encoding-the-cardiac-sodium-channel-and-associated-compounds-and-their-impact-on-outcome-of-catheter-ablation-of-atrial-fibrillation
#15
Daniela Husser, Laura Ueberham, Gerhard Hindricks, Petra Büttner, Christie Ingram, Peter Weeke, M Benjamin Shoemaker, Volker Adams, Arash Arya, Philipp Sommer, Dawood Darbar, Dan M Roden, Andreas Bollmann
AIM: Rare variants of genes encoding the cardiac sodium channel and associated compounds have been linked with atrial fibrillation (AF). Nevertheless, current expert consensus does not support genetic testing in AF, which is in part based on the fact that "there is no therapeutic impact derived from AF genetic test results". However, there are no studies available supporting this recommendation. Consequently, this study analyzed the impact of rare variants affecting the cardiac sodium channel on rhythm outcome of AF catheter ablation...
2017: PloS One
https://www.readbyqxmd.com/read/28815794/finding-the-candidate-sequence-variants-for-diagnosis-of-hypertrophic-cardiomyopathy-in-east-slovak-patients
#16
Michaela Zigova, Jarmila Bernasovska, Iveta Boronova, Marta Mydlarova Blascakova, Jan Kmec
BACKGROUND: Hypertrophic cardiomyopathy is a heterogeneous myocardial disease. Mutations appearing in several genes might be a potential cause of the disease. The aim of the study was to analyze selected exons of the sarcomeric and non-sarcomeric genes, with the purpose to identify potential candidate genetic variants and to understand etiopathogenetic mechanisms of hypertrophic cardiomyopathy in East Slovak patients. METHODS: This study recruited 23 unrelated patients with hypertrophic cardiomyopathy, namely, 13 men and 10 women (mean age of 58...
August 16, 2017: Journal of Clinical Laboratory Analysis
https://www.readbyqxmd.com/read/28782696/heritability-in-a-scn5a-mutation-founder-population-with-increased-female-susceptibility-to-non-nocturnal-ventricular-tachyarrhythmia-and-sudden-cardiac-death
#17
Rachel M A Ter Bekke, Aaron Isaacs, Andrei Barysenka, Marije B Hoos, Jan D H Jongbloed, Jan C A Hoorntje, Alfons S M Patelski, Apollonia T J M Helderman-van den Enden, Arthur van den Wijngaard, Monika Stoll, Paul G A Volders
BACKGROUND: Heritable cardiac-sodium channel dysfunction is associated with various arrhythmia syndromes, some predisposing to ventricular fibrillation. Phenotypic diversity among carriers of identical-by-descent mutations is often remarkable, suggesting influences of genetic modifiers. OBJECTIVE: The purpose of this study was to identify a unique SCN5A-mutation founder population with mixed clinical phenotypes and sudden cardiac death, and to investigate the heritability of electromechanical traits besides the SCN5A-mutation effect...
August 3, 2017: Heart Rhythm: the Official Journal of the Heart Rhythm Society
https://www.readbyqxmd.com/read/28781849/double-jeopardy-long-qt3-and-brugada-syndromes
#18
Amneet Sandhu, Ryan T Borne, Chandara Mam, T Jared Bunch, Ryan G Aleong
Mutations in the SCN5A gene are linked to both the long QT syndrome 3 and Brugada syndrome with few reports describing an overlapping phenotype. We present a unique case and discuss clinical considerations of a patient concurrently exhibiting such conditions with genetic analysis confirming an SCN5A mutation.
August 2017: Clinical Case Reports
https://www.readbyqxmd.com/read/28734073/differential-calcium-sensitivity-in-nav-1-5-mixed-syndrome-mutants
#19
Mena Abdelsayed, Alban-Elouen Baruteau, Karen Gibbs, Shubhayan Sanatani, Andrew D Krahn, Vincent Probst, Peter C Ruben
KEY POINTS: SCN5a mutations may express gain-of-function (Long QT Syndrome-3), loss-of-function (Brugada Syndrome 1) or both (mixed syndromes), depending on the mutation and environmental triggers. One such trigger may be an increase in cytosolic calcium, accompanying exercise. Many mixed syndromes mutants, including ∆KPQ, E1784K, 1795insD and Q1909R, are found in calcium-sensitive regions. Elevated cytosolic calcium attenuates gain-of-function properties in ∆KPQ, 1795insD and Q1909R, but not in E1784K...
September 15, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28725320/splice-site-variants-in-the-kcnq1-and-scn5a-genes-transcript-analysis-as-a-tool-in-supporting-pathogenicity
#20
Ivone U S Leong, Philippa A Dryland, Debra O Prosser, Stella W-S Lai, Mandy Graham, Martin Stiles, Jackie Crawford, Jonathan R Skinner, Donald R Love
BACKGROUND: Approximately 75% of clinically definite long QT syndrome (LQTS) cases are caused by mutations in the KCNQ1, KCNH2 and SCN5A genes. Of these mutations, a small proportion (3.2-9.2%) are predicted to affect splicing. These mutations present a particular challenge in ascribing pathogenicity. METHODS: Here we report an analysis of the transcriptional consequences of two mutations, one in the KCNQ1 gene (c.781_782delinsTC) and one in the SCN5A gene (c.2437-5C>A), which are predicted to affect splicing...
August 2017: Journal of Clinical Medicine Research
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