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SCN5A Mutations

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https://www.readbyqxmd.com/read/29032483/regulation-of-cardiac-voltage-gated-sodium-channel-by-kinases-roles-of-protein-kinases-a-and-c
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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
https://www.readbyqxmd.com/read/28704380/molecular-investigation-by-whole-exome-sequencing-revealed-a-high-proportion-of-pathogenic-variants-among-thai-victims-of-sudden-unexpected-death-syndrome
#12
Bhoom Suktitipat, Sakda Sathirareuangchai, Ekkapong Roothumnong, Wanna Thongnoppakhun, Purin Wangkiratikant, Nutchavadee Vorasan, Rungroj Krittayaphong, Manop Pithukpakorn, Warangkna Boonyapisit
INTRODUCTION: Sudden unexpected death syndrome (SUDS) is an important cause of death in young healthy adults with a high incident rate in Southeast Asia; however, there are no molecular autopsy reports about these victims. We performed a combination of both a detailed autopsy and a molecular autopsy by whole exome sequencing (WES) to investigate the cause of SUDS in Thai sudden death victims. MATERIALS AND METHODS: A detailed forensic autopsy was performed to identify the cause of death, followed by a molecular autopsy, in 42 sudden death victims who died between January 2015 and August 2015...
2017: PloS One
https://www.readbyqxmd.com/read/28701297/genomic-analysis-of-an-infant-with-intractable-diarrhea-and-dilated-cardiomyopathy
#13
Dale L Bodian, Thierry Vilboux, Suchitra K Hourigan, Callie L Jenevein, Haresh Mani, Kathleen C Kent, Alina Khromykh, Benjamin D Solomon, Natalie S Hauser
We describe a case of an infant presenting with intractable diarrhea who subsequently developed dilated cardiomyopathy, for whom a diagnosis was not initially achieved despite extensive clinical testing, including panel-based genetic testing. Research-based whole genome sequences of the proband and both parents were analyzed by the SAVANNA pipeline, a variant prioritization strategy integrating features of variants, genes, and phenotypes, which was implemented using publicly available tools. Although the intestinal morphological abnormalities characteristic of congenital tufting enteropathy (CTE) were not observed in the initial clinical gastrointestinal tract biopsies of the proband, an intronic variant, EPCAM c...
July 12, 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28637969/development-of-a-patient-derived-induced-pluripotent-stem-cell-model-for-the-investigation-of-scn5a-d1275n-related-cardiac-sodium-channelopathy
#14
Mamoru Hayano, Takeru Makiyama, Tsukasa Kamakura, Hiroshi Watanabe, Kenichi Sasaki, Shunsuke Funakoshi, Yimin Wuriyanghai, Suguru Nishiuchi, Takeshi Harita, Yuta Yamamoto, Hirohiko Kohjitani, Sayako Hirose, Fumika Yokoi, Jiarong Chen, Osamu Baba, Takahiro Horie, Kazuhisa Chonabayashi, Seiko Ohno, Futoshi Toyoda, Yoshinori Yoshida, Koh Ono, Minoru Horie, Takeshi Kimura
BACKGROUND: TheSCN5Agene encodes the α subunit of the cardiac voltage-gated sodium channel, NaV1.5. The missense mutation, D1275N, has been associated with a range of unusual phenotypes associated with reduced NaV1.5 function, including cardiac conduction disease and dilated cardiomyopathy. Curiously, the reported biophysical properties ofSCN5A-D1275N channels vary with experimental system.Methods and Results:First, using a human embryonic kidney (HEK) 293 cell-based heterologous expression system, theSCN5A-D1275N channels showed similar maximum sodium conductance but a significantly depolarizing shift of activation gate (+10 mV) compared to wild type...
June 20, 2017: Circulation Journal: Official Journal of the Japanese Circulation Society
https://www.readbyqxmd.com/read/28597987/trafficking-and-localization-to-the-plasma-membrane-of-nav-1-5-promoted-by-the-%C3%AE-2-subunit-is-defective-due-to-a-%C3%AE-2-mutation-associated-with-brugada-syndrome
#15
Gemma Dulsat, Sonia Palomeras, Eric Cortada, Helena Riuró, Ramon Brugada, Marcel Vergés
BACKGROUND INFORMATION: Cardiac channelopathies arise by mutations in genes encoding ion channel subunits. One example is Brugada Syndrome (BrS), which causes arrhythmias and sudden death. BrS is often associated with mutations in SCN5A, encoding Nav 1.5, the α subunit of the major cardiac voltage-gated sodium channel. This channel forms a protein complex including one or two associated β subunits as well as other proteins. RESULTS: We analyzed regulation of Nav 1...
June 9, 2017: Biology of the Cell
https://www.readbyqxmd.com/read/28557294/a-mechanism-for-nav-1-5-downregulation-and-sodium-current-decrease-in-heart-failure
#16
EDITORIAL
S Pagans, M Vergés
No abstract text is available yet for this article.
September 2017: Acta Physiologica
https://www.readbyqxmd.com/read/28552050/readthrough-of-scn5a-nonsense-mutations-r1623x-and-s1812x-question-gene-therapy-in-brugada-syndrome
#17
Siyong Teng, Jian Huang, Zhan Gao, Jie Hao, Yuejin Yang, Shu Zhang, Jielin Pu, Rutai Hui, Yongjian Wu, Zheng Fan
PURPOSE: Readthrough of nonsense mutation are used as gene-specific treatment in some genetic disease. Response to readthrough treatment is determined by readthrough efficiency of various nonsense mutations. In this manuscript, we aimed to explore the harmful effect of nonsense mutation suppressions. METHODS: HEK293 cells were transfected with two SCN5A (encode cardiac Na+ channel) nonsense mutations, p.R1623X and p.S1812X. We applied two readthrough-enhancing methods (either aminoglycosides or by a siRNA targeting eukaryotic release factor eRF3a (a GTPase that binds eRF1)) to suppress these SCN5A nonsense mutations...
May 28, 2017: Current Gene Therapy
https://www.readbyqxmd.com/read/28534967/whole%C3%A2-exome-sequencing-identifies-a-novel-mutation-r367g-in-scn5a-to-be-associated-with-familial-cardiac-conduction-disease
#18
Rong Yu, Xue-Feng Fan, Chan Chen, Zheng-Hua Liu
Cardiac conduction disease is a primary cause of sudden cardiac death. Sodium voltage‑gated channel‑α subunit 5 (SCN5A) mutations have been reported to underlie a variety of inherited arrhythmias. Numerous disease‑causing mutations of SCN5A have been identified in patients with ≥10 different conditions, including type 3 long‑QT syndrome and Brugada syndrome. The present study investigated a family with a history of arrhythmia, with the proband having a history of arrhythmia and syncope. Whole‑exome sequencing was applied in order to detect the disease‑causing mutation in this family, and Sanger sequencing was used to confirm the co‑segregation among the family members...
July 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28494446/mutation-load-of-multiple-ion-channel-gene-mutations-in-brugada-syndrome
#19
Francesca Gualandi, Fatima Zaraket, Michele Malagù, Giulia Parmeggiani, Cecilia Trabanelli, Sergio Fini, Xiao Dang, Xiaoming Wei, Mingyan Fang, Matteo Bertini, Roberto Ferrari, Alessandra Ferlini
Brugada syndrome is a primary arrhythmic syndrome that accounts for 20% of all sudden cardiac death cases in individuals with a structurally normal heart. Pathogenic variants associated with Brugada syndrome have been identified in over 19 genes, with SCN5A as a pivotal gene accounting for nearly 30% of cases. In contrast to other arrhythmogenic channelopathies (such as long QT syndrome), digenic inheritance has never been reported in Brugada syndrome. Exploring 66 cardiac genes using a new custom next-generation sequencing panel, we identified a double heterozygosity for pathogenic mutations in SCN5A and TRPM4 in a Brugada syndrome patient...
2017: Cardiology
https://www.readbyqxmd.com/read/28493952/a-mutation-in-the-cacna1c-gene-leads-to-early-repolarization-syndrome-with-incomplete-penetrance-a-chinese-family-study
#20
Xin Liu, Yang Shen, Jinyan Xie, Huihui Bao, Qing Cao, Rong Wan, Xiaoming Xu, Hui Zhou, Lin Huang, Zhenyan Xu, Wengen Zhu, Jinzhu Hu, Xiaoshu Cheng, Kui Hong
BACKGROUND: Early repolarization syndrome (ERS) may be a near-Mendelian or an oligogenic disease; however, no direct evidence has been provided to support this theory. METHODS AND RESULTS: We described a large Chinese family with nocturnal sudden cardiac death induced by ERS in most of the young male adults. One missense mutation (p.Q1916R) was found in the major subunit of the L-type calcium channel gene CACNA1C by the direct sequencing of candidate genes. A concomitant gain-of-function variant in the sodium channel gene SCN5A (p...
2017: PloS One
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