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SCN5A Mutations

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https://www.readbyqxmd.com/read/28438721/clinical-profile-and-mutation-spectrum-of-long-qt-syndrome-in-saudi-arabia-the-impact-of-consanguinity
#1
Zuhair N Al-Hassnan, Majid Al-Fayyadh, Bander Al-Ghamdi, Azam Shafquat, Yaseen Mallawi, Faten Al-Hadeq, Sahar Tulbah, Zarghuna Ma Shinwari, Abdulrahman Almesned, Ali Alakhfash, Fadel Al Fadly, Ahmed S Hersi, Abdullah Alhayani, Amal Al-Hashem, Dia Arafah, Nduna Dzimiri, Brian Meyer, Monther Rababh, Waleed Al-Manea
BACKGROUND: Congenital long QT syndrome (LQTS) is an inherited potentially fatal arrhythmogenic disorder. At least 16 genes have been implicated in LQTS; the yield of genetic analysis of 3 genes (KCNQ1, KCNH2, and SCN5A) is about 70% with KCNQ1 mutations accounting for ∼50% of positive cases. LQTS is mostly inherited in an autosomal dominant pattern. Systemic analysis of LQTS has not been previously conducted in a population with a high degree of consanguinity. OBJECTIVES: We aim to describe the clinical and molecular profiles of LQTS in the highly consanguineous Saudi population...
April 21, 2017: Heart Rhythm: the Official Journal of the Heart Rhythm Society
https://www.readbyqxmd.com/read/28430892/anti-arrhythmic-potential-of-the-late-sodium-current-inhibitor-gs-458967-in-murine-scn5a-1798insd-and-human-scn5a-1795insd-ipsc-derived-cardiomyocytes
#2
Vincent Portero, Simona Casini, Maaike Hoekstra, Arie O Verkerk, Isabella Mengarelli, Luiz Belardinelli, Sridharan Rajamani, Arthur A M Wilde, Connie R Bezzina, Marieke W Veldkamp, Carol Ann Remme
AIM: Selective inhibition of cardiac late sodium current (INaL) is an emerging target in the treatment of ventricular arrhythmias. We investigated the electrophysiological effects of GS-458967 (GS967), a potent, selective inhibitor of INaL, in an overlap syndrome model of both gain and loss of sodium channel function, comprising cardiomyocytes derived from both human SCN5A-1795insD+/- induced pluripotent stem cells (hiPSC-CMs) and mice carrying the homologous mutation Scn5a-1798insD+/-...
April 18, 2017: Cardiovascular Research
https://www.readbyqxmd.com/read/28412158/lidocaine-attenuation-testing-an-in-vivo-investigation-of-putative-lqt3-associated-variants-in-the-scn5a-encoded-sodium-channel
#3
M D Heather N Anderson, J Martijn Bos, Jamie D Kapplinger, Jana M Meskill, Dan Ye, Michael J Ackerman
BACKGROUND: Long QT type 3 (LQT3) accounts for 5-10% of LQTS and results from gain-of-function mutations in the SCN5A-encoded sodium channel. Nearly 2% of healthy individuals host rare SCN5A variants of uncertain significance (VUS). Distinction of true LQT3-causative mutations from background genetic noise is essential. OBJECTIVE: This study was designed to assess the utility of the lidocaine attenuation test (LAT) in evaluating patients with possible LQT3. METHODS: We reviewed LAT results and medical records for 25 patients with a possible LQT3-associated SCN5A variant...
April 12, 2017: Heart Rhythm: the Official Journal of the Heart Rhythm Society
https://www.readbyqxmd.com/read/28404070/pathophysiology-of-irritable-bowel-syndrome
#4
REVIEW
Gerald J Holtmann, Alexander C Ford, Nicholas J Talley
Traditionally, irritable bowel syndrome has been considered to be a disorder with no known underlying structural or biochemical explanation, but this concept is likely to be outdated. In this Review we challenge the widely accepted view that irritable bowel syndrome is an unexplained brain-gut disorder. There is epidemiological evidence that, in a major subset of patients, gastrointestinal symptoms arise first and only later do incident mood disorders occur. Additionally, possible mechanisms for gut-brain dysfunction have been identified, suggesting primary gut disturbances might be the underlying cause in a subgroup...
October 2016: Lancet. Gastroenterology & Hepatology
https://www.readbyqxmd.com/read/28391114/genotype-phenotype-dilemma-in-a-case-of-sudden-cardiac-death-with-the-e1053k-mutation-and-a-deletion-in-the-scn5a-gene
#5
T Jenewein, B M Beckmann, S Rose, H H Osterhues, U Schmidt, C Wolpert, P Miny, C Marschall, M Alders, C R Bezzina, A A M Wilde, S Kääb, S Kauferstein
Mutations in the cardiac sodium channel gene SCN5A may result in various arrhythmia syndromes such as long QT syndrome type 3 (LQTS), Brugada syndrome (BrS), sick sinus syndrome (SSS), cardiac conduction diseases (CCD) and possibly dilated cardiomyopathy (DCM). In most of these inherited cardiac arrhythmia syndromes the phenotypical expression may range from asymptomatic phenotypes to sudden cardiac death (SCD). A 16-year-old female died during sleep. Autopsy did not reveal any explanation for her death and a genetic analysis was performed...
March 20, 2017: Forensic Science International
https://www.readbyqxmd.com/read/28373245/an-east-asian-common-variant-vinculin-p-asp841his-was-associated-with-sudden-unexplained-nocturnal-death-syndrome-in-the-chinese-han-population
#6
Jianding Cheng, John W Kyle, Di Lang, Brandi Wiedmeyer, Jian Guo, Kun Yin, Lei Huang, Ravi Vaidyanathan, Terry Su, Jonathan C Makielski
BACKGROUND: We have identified the cardiomyopathy-susceptibility gene vinculin (VCL) mutation M94I may account for a sudden unexplained nocturnal death syndrome (SUNDS) case. We addressed whether VCL common variant D841H is associated with SUNDS. METHODS AND RESULTS: In 8 of 120 SUNDS cases, we detected an East Asian common VCL variant p.Asp841His (D841H). Comparing the H841 allele frequency of the general population in the local database (15 of 1818) with SUNDS victims (10 of 240) gives an odds ratio for SUNDS of 5...
April 3, 2017: Journal of the American Heart Association
https://www.readbyqxmd.com/read/28370132/infant-sudden-death-mutations-responsible-for-impaired-nav1-5-channel-trafficking-and-function
#7
Ivan Gando, Jace Morganstein, Kundan Jana, Thomas V McDonald, Yingying Tang, William A Coetzee
BACKGROUND: Two genetic variants in SCN5A, encoding the Nav1.5 Na(+) channel α-subunit, were found in a five month-old girl who died suddenly in her sleep. The first variant is a missense mutation, resulting in an amino acid change (Q1832E), which has been described (but not characterized) in a patient with Brugada syndrome. The second is a nonsense mutation that produces a premature stop codon and a C-terminal truncation (R1944Δ). METHODS AND RESULTS: To investigate their functional relevance with patch clamp experiments in transfected HEK293 cells...
March 31, 2017: Pacing and Clinical Electrophysiology: PACE
https://www.readbyqxmd.com/read/28341781/genotype-phenotype-correlation-of-scn5a-mutation-for-the-clinical-and-electrocardiographic-characteristics-of-probands-with-brugada-syndrome-a-japanese-multicenter-registry
#8
Kenichiro Yamagata, Minoru Horie, Takeshi Aiba, Satoshi Ogawa, Yoshifusa Aizawa, Toru Ohe, Masakazu Yamagishi, Naomasa Makita, Harumizu Sakurada, Toshihiro Tanaka, Akihiko Shimizu, Nobuhisa Hagiwara, Ryoji Kishi, Yukiko Nakano, Masahiko Takagi, Takeru Makiyama, Seiko Ohno, Keiichi Fukuda, Hiroshi Watanabe, Hiroshi Morita, Kenshi Hayashi, Kengo Kusano, Shiro Kamakura, Satoshi Yasuda, Hisao Ogawa, Yoshihiro Miyamoto, Jamie D Kapplinger, Michael J Ackerman, Wataru Shimizu
Background -The genotype-phenotype correlation of SCN5A mutations as a predictor of cardiac events in Brugada syndrome remains controversial. We aimed to establish a registry limited to probands, with a long follow-up period, so that the genotype-phenotype correlation of SCN5A mutations in Brugada syndrome can be examined without patient selection bias. Methods -This multicenter registry enrolled 415 probands (n=403; men, 97%; age, 46±14 years) diagnosed with Brugada syndrome whose SCN5A gene was analyzed for mutations...
March 24, 2017: Circulation
https://www.readbyqxmd.com/read/28339995/long-term-flecainide-therapy-in-type-3-long-qt-syndrome
#9
Ehud Chorin, Rivki Taub, Aron Medina, Nir Flint, Sami Viskin, Jesaia Benhorin
Aims: Type 3 long QT syndrome (LQT3) is caused by gain-of-function mutations in the cardiac sodium channel gene (SCN5A). Previous reports on the long-term use of sodium channel blockers in LQT3 are sparse. The objective of the current study was to evaluate the long-term safety and efficacy of flecainide therapy in patients with LQT3 who carry the D1790G SCN5A mutation. Methods and results: The study population comprised 30 D1790G carriers who were treated with flecainide and followed for 1-215 months (mean 145 ± 54 months, median 140 months)...
February 28, 2017: Europace: European Pacing, Arrhythmias, and Cardiac Electrophysiology
https://www.readbyqxmd.com/read/28339646/transforming-growth-factor-%C3%AE-receptor-inhibition-prevents-ventricular-fibrosis-in-a-mouse-model-of-progressive-cardiac-conduction-disease
#10
Mickael Derangeon, Jérôme Montnach, Cynthia Ore Cerpa, Benoit Jagu, Justine Patin, Gilles Toumaniantz, Aurore Girardeau, Christopher L H Huang, William H Colledge, Andrew A Grace, Isabelle Baró, Flavien Charpentier
Aims: Loss-of-function mutations in SCN5A, the gene encoding NaV1.5 channel, have been associated with inherited progressive cardiac conduction disease (PCCD). We have proposed that Scn5a heterozygous knock-out (Scn5a+/-) mice, which are characterized by ventricular fibrotic remodelling with ageing, represent a model for PCCD. Our objectives were to identify the molecular pathway involved in fibrosis development and prevent its activation. Methods and results: Our study shows that myocardial interstitial fibrosis occurred in Scn5a+/- mice only after 45 weeks of age...
April 1, 2017: Cardiovascular Research
https://www.readbyqxmd.com/read/28336205/andersen-tawil-syndrome-clinical-presentation-and-predictors-of-symptomatic-arrhythmias-possible-role-of-polymorphisms-k897t-in-kcnh2-and-h558r-in-scn5a-gene
#11
Michalina Krych, Elżbieta Katarzyna Biernacka, Joanna Ponińska, Piotr Kukla, Artur Filipecki, Robert Gajda, Can Hasdemir, Charles Antzelevitch, Agnieszka Kosiec, Małgorzata Szperl, Rafał Płoski, Maria Trusz-Gluza, Katarzyna Mizia-Stec, Piotr Hoffman
BACKGROUND: Andersen-Tawil syndrome (ATS) is rare channelopathy caused by KCNJ2 mutation and probably KCNJ5. It is characterized by arrhythmias, neurological symptoms, and dysmorphic features. The present study retrospectively examined the characteristics of 11 unrelated families with ATS. METHODS: This study consisted of 11 probands positive for KCNJ2 variants and 33 family members (mean age 30.0±17.3 years, female n=31). Additional genetic screening of 3 LQTS genes (KCNQ1, KCNH2, SCN5A) was performed in 9 families...
March 20, 2017: Journal of Cardiology
https://www.readbyqxmd.com/read/28315637/trpm4-non-selective-cation-channel-variants-in-long-qt-syndrome
#12
Thomas Hof, Hui Liu, Laurent Sallé, Jean-Jacques Schott, Corinne Ducreux, Gilles Millat, Philippe Chevalier, Vincent Probst, Romain Guinamard, Patrice Bouvagnet
BACKGROUND: Long QT syndrome (LQTS) is an inherited arrhythmic disorder characterized by prolongation of the QT interval, a risk of syncope, and sudden death. There are already a number of causal genes in LQTS, but not all LQTS patients have an identified mutation, which suggests LQTS unknown genes. METHODS: A cohort of 178 LQTS patients, with no mutations in the 3 major LQTS genes (KCNQ1, KCNH2, and SCN5A), was screened for mutations in the transient potential melastatin 4 gene (TRPM4)...
March 18, 2017: BMC Medical Genetics
https://www.readbyqxmd.com/read/28294644/electrocardiogram-changes-and-atrial-arrhythmias-in-individuals-carrying-sodium-channel-scn5a-d1275n-mutation
#13
Sari U M Vanninen, Kjell Nikus, Katriina Aalto-Setälä
INTRODUCTION: The cardiac sodium channel SCN5A regulates atrioventricular and ventricular depolarization as well as cardiac conduction. Patients with cardiac electrical abnormalities have an increased risk of sudden cardiac death (SCD) and cardio-embolic stroke. Optimal management of cardiac disease includes the understanding of association between the causative mutations and the clinical phenotype. A 12-lead electrocardiogram (ECG) is an easy and inexpensive tool for finding risk patients...
March 15, 2017: Annals of Medicine
https://www.readbyqxmd.com/read/28262340/gain-of-function-mutation-in-scn5a-causes-ventricular-arrhythmias-and-early-onset-atrial-fibrillation
#14
Krystien V Lieve, Arie O Verkerk, Svitlana Podliesna, Christian van der Werf, Michael W Tanck, Nynke Hofman, Paul F van Bergen, Leander Beekman, Connie R Bezzina, Arthur A M Wilde, Elisabeth M Lodder
BACKGROUND: Mutations in SCN5A, the gene encoding the α-subunit of the cardiac sodium channel (NaV1.5), are associated with a broad spectrum of inherited cardiac arrhythmia disorders. The purpose of this study was to identify the genetic and functional determinants underlying a Dutch family that presented with a combined phenotype of ventricular arrhythmias with a likely adrenergic component, either in isolation or in combination with a mildly decreased heart function and early onset (<55years) atrial fibrillation...
January 29, 2017: International Journal of Cardiology
https://www.readbyqxmd.com/read/28218286/vinculin-variant-m94i-identified-in-sudden-unexplained-nocturnal-death-syndrome-decreases-cardiac-sodium-current
#15
Jianding Cheng, John W Kyle, Brandi Wiedmeyer, Di Lang, Ravi Vaidyanathan, Jonathan C Makielski
Sudden unexplained nocturnal death syndrome (SUNDS) remains an autopsy negative disorder with unclear etiology. Vinculin (VCL) was linked to sudden arrhythmia death in VCL knockout mice prior to the appearance of cardiomyopathy. We hypothesized VCL mutations underlie risk for SUNDS. A rare heterozygous variant VCL-M94I was found in a SUNDS victim who suffered sudden nocturnal tachypnea and lacked pathogenic variants in known arrhythmia-causing genes. VCL was identified to interact with SCN5A in vitro/vivo. The VCL-M94I was co-expressed with the cardiac sodium channel in HEK293 cells and also overexpressed in induced pluripotent stem cells derived cardiomyocytes (iPSCs-CM)...
February 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28217227/cardiac-conduction-defects-and-brugada-syndrome-a-family-with-overlap-syndrome-carrying-a-nonsense-scn5a-mutation
#16
Hisaaki Aoki, Yoshihide Nakamura, Seiko Ohno, Takeru Makiyama, Minoru Horie
BACKGROUND: Phenotypes often differ even within family members carrying the same SCN5A mutation. We aimed to evaluate the genetic modifiers in a family with Brugada syndrome (BrS) and sick sinus syndrome (SSS) with an SCN5A mutation that causes the truncated alpha-subunit of cardiac Na channel protein. METHODS: To detect the genetic modifiers, we performed targeted panel sequencing of the coding region of 46 genes that are related to primary arrhythmia syndrome, by using a bench-top, next generation sequencer...
February 2017: Journal of Arrhythmia
https://www.readbyqxmd.com/read/28191886/sirtuin-1-regulates-cardiac-electrical-activity-by-deacetylating-the-cardiac-sodium-channel
#17
Ajit Vikram, Christopher M Lewarchik, Jin-Young Yoon, Asma Naqvi, Santosh Kumar, Gina M Morgan, Julia S Jacobs, Qiuxia Li, Young-Rae Kim, Modar Kassan, Jing Liu, Mohanad Gabani, Ajay Kumar, Haider Mehdi, Xiaodong Zhu, Xiaoqun Guan, William Kutschke, Xiaoming Zhang, Ryan L Boudreau, Shengchuan Dai, Daniel S Matasic, Saet-Byel Jung, Kenneth B Margulies, Vikas Kumar, Markus M Bachschmid, Barry London, Kaikobad Irani
The voltage-gated cardiac Na(+) channel (Nav1.5), encoded by the SCN5A gene, conducts the inward depolarizing cardiac Na(+) current (INa) and is vital for normal cardiac electrical activity. Inherited loss-of-function mutations in SCN5A lead to defects in the generation and conduction of the cardiac electrical impulse and are associated with various arrhythmia phenotypes. Here we show that sirtuin 1 deacetylase (Sirt1) deacetylates Nav1.5 at lysine 1479 (K1479) and stimulates INa via lysine-deacetylation-mediated trafficking of Nav1...
March 2017: Nature Medicine
https://www.readbyqxmd.com/read/28185290/computational-analysis-of-the-human-sinus-node-action-potential-model-development-and-effects-of-mutations
#18
Alan Fabbri, Matteo Fantini, Ronald Wilders, Stefano Severi
KEY POINTS: We constructed a comprehensive mathematical model of the spontaneous electrical activity of a human sinoatrial node (SAN) pacemaker cell, starting from the recent Severi-DiFrancesco model of rabbit SAN cells. Our model is based on electrophysiological data from isolated human SAN pacemaker cells and closely matches the action potentials and calcium transient that were recorded experimentally. Simulated ion channelopathies explain the clinically observed changes in heart rate in corresponding mutation carriers, providing an independent qualitative validation of the model...
April 1, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28159958/p-n1380del-mutation-in-the-pore-forming-region-of-scn5a-gene-is-associated-with-cardiac-conduction-disturbance-and-ventricular-tachycardia
#19
Zhen Yang, Danbo Lu, Lei Zhang, Jialu Hu, Zhenning Nie, Chang Xie, Fang Qiu, Hua Cheng, Yan Yan
No abstract text is available yet for this article.
February 4, 2017: Acta Biochimica et Biophysica Sinica
https://www.readbyqxmd.com/read/28146213/compound-heterozygous-scn5a-mutations-in-a-toddler-are-they-associated-with-a-more-severe-phenotype
#20
Luciana Sacilotto, Hindalis Ballesteros Epifanio, Francisco Carlos da Costa Darrieux, Fanny Wulkan, Theo Gremen Mimary Oliveira, Denise Tessariol Hachul, Alexandre da Costa Pereira, Mauricio Ibrahim Scanavacca
Compound heterozygosity has been described in inherited arrhythmias, and usually associated with a more severe phenotype. Reports of this occurrence in Brugada syndrome patients are still rare. We report a study of genotype-phenotype correlation after the identification of new variants by genetic testing. We describe the case of an affected child with a combination of two different likely pathogenic SCN5A variants, presenting sinus node dysfunction, flutter and atrial fibrillation, prolonged HV interval, spontaneous type 1 Brugada pattern in the prepubescent age and familiar history of sudden death...
January 2017: Arquivos Brasileiros de Cardiologia
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