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ion channelopathy

Maroua Boukhabza, Jaouad El Hilaly, Nourdine Attiya, Ahmed El-Haidani, Younes Filali-Zegzouti, Driss Mazouzi, Mohamed-Yassine Amarouch
Ion channels are transmembrane proteins that allow the passage of ions according to the direction of their electrochemical gradients. Mutations in more than 30 genes encoding ion channels have been associated with an increasingly wide range of inherited cardiac arrhythmias. In this line, ion channels become one of the most important molecular targets for several classes of drugs, including antiarrhythmics. Nevertheless, antiarrhythmic drugs are usually accompanied by some serious side effects. Thus, developing new approaches could offer added values to prevent and treat the episodes of arrhythmia...
2016: Computational and Mathematical Methods in Medicine
Ramon Latorre, Karen Castillo, Willy Carrasquel-Ursulaez, Romina V Sepulveda, Fernando Gonzalez-Nilo, Carlos Gonzalez, Osvaldo Alvarez
Large-conductance Ca(2+)- and voltage-activated K(+) (BK) channels play many physiological roles ranging from the maintenance of smooth muscle tone to hearing and neurosecretion. BK channels are tetramers in which the pore-forming α subunit is coded by a single gene (Slowpoke, KCNMA1). In this review, we first highlight the physiological importance of this ubiquitous channel, emphasizing the role that BK channels play in different channelopathies. We next discuss the modular nature of BK channel-forming protein, in which the different modules (the voltage sensor and the Ca(2+) binding sites) communicate with the pore gates allosterically...
January 2017: Physiological Reviews
Jaeyong Han, Seung Hun Lee, Gerhard Giebisch, Tong Wang
Potassium channels and transporters maintain potassium homeostasis and play significant roles in several different biological actions via potassium ion regulation. In previous decades, the key revelations that potassium channels and transporters are involved in the production of gastric acid and the regulation of secretion in the stomach have been recognized. Drugs used to treat peptic ulceration are often potassium transporter inhibitors. It has also been reported that potassium channels are involved in ulcerative colitis...
November 15, 2016: Gut and Liver
Lois Choy, Jie Ming Yeo, Vivian Tse, Shing Po Chan, Gary Tse
The mouse is the second mammalian species, after the human, in which substantial amount of the genomic information has been analyzed. With advances in transgenic technology, mutagenesis is now much easier to carry out in mice. Consequently, an increasing number of transgenic mouse systems have been generated for the study of cardiac arrhythmias in ion channelopathies and cardiomyopathies. Mouse hearts are also amenable to physical manipulation such as coronary artery ligation and transverse aortic constriction to induce heart failure, radiofrequency ablation of the AV node to model complete AV block and even implantation of a miniature pacemaker to induce cardiac dyssynchrony...
September 2016: IJC Heart & Vasculature
Yuka Mizusawa
Inherited arrhythmias, such as cardiomyopathies and cardiac ion channelopathies, along with coronary heart disease (CHD) are three most common disorders that predispose adults to sudden cardiac death. In the last three decades, causal genes in inherited arrhythmias have been successfully identified. At the same time, it has become evident that the genetic architectures are more complex than previously known. Recent advancements in DNA sequencing technology (next generation sequencing) have enabled us to study such complex genetic traits...
October 2016: Journal of Arrhythmia
Thomas M Roston, Wenting Guo, Andrew D Krahn, Ruiwu Wang, Filip Van Petegem, Shubhayan Sanatani, S R Wayne Chen, Anna Lehman
BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an ion channelopathy usually caused by gain-of-function mutations ryanodine receptor type-2 (RyR2). Left ventricular non-compaction (LVNC) is an often genetic cardiomyopathy. A rare LVNC-CPVT overlap syndrome may be caused by exon 3 deletion in RyR2. We sought to characterize the phenotypic spectrum and molecular basis of a novel RyR2 mutation identified in a family with both conditions. METHODS: Several members of an affected family underwent clinical and genetic assessments...
September 8, 2016: Journal of Electrocardiology
P B Persson, A Bondke Persson
No abstract text is available yet for this article.
November 2016: Acta Physiologica
Eric G Bend, Yue Si, David A Stevenson, Pinar Bayrak-Toydemir, Tara M Newcomb, Erik M Jorgensen, Kathryn J Swoboda
OBJECTIVE: To perform genotype-phenotype analysis in an infant with congenital arthrogryposis due to a de novo missense mutation in the NALCN ion channel and explore the mechanism of pathogenicity using a Caenorhabditis elegans model. METHODS: We performed whole-exome sequencing in a preterm neonate with congenital arthrogryposis and a severe life-threatening clinical course. We examined the mechanism of pathogenicity of the associated NALCN mutation by engineering the orthologous mutation into the nematode C elegans using CRISPR-Cas9...
September 13, 2016: Neurology
Arthur Beyder, Gianrico Farrugia
In the gastrointestinal (GI) tract, abnormalities in secretion, absorption, motility, and sensation have been implicated in functional gastrointestinal disorders (FGIDs). Ion channels play important roles in all these GI functions. Disruptions of ion channels' ability to conduct ions can lead to diseases called ion channelopathies. Channelopathies can result from changes in ion channel biophysical function or expression due to mutations, posttranslational modification, and accessory protein malfunction. Channelopathies are strongly established in the fields of cardiology and neurology, but ion channelopathies are only beginning to be recognized in gastroenterology...
October 1, 2016: American Journal of Physiology. Gastrointestinal and Liver Physiology
Simona Pellacani, Federico Sicca, Cherubino Di Lorenzo, Gaetano S Grieco, Giulia Valvo, Cristina Cereda, Anna Rubegni, Filippo M Santorelli
Channelopathies are a heterogeneous group of neurological disorders resulting from dysfunction of ion channels located in cell membranes and organelles. The clinical scenario is broad and symptoms such as generalized epilepsy (with or without fever), migraine (with or without aura), episodic ataxia and periodic muscle paralysis are some of the best known consequences of gain- or loss-of-function mutations in ion channels. We review the main clinical effects of ion channel mutations associated with a significant impact on migraine headache...
2016: Frontiers in Cellular Neuroscience
Pietro Mesirca, Isabelle Bidaud, Matteo E Mangoni
Pacemaker activity of the sino-atrial node generates the heart rate. Disease of the sinus node and impairment of atrioventricular conduction induce an excessively low ventricular rate (bradycardia), which cannot meet the needs of the organism. Bradycardia accounts for about half of the total workload of clinical cardiologists. The 'sick sinus' syndrome (SSS) is characterized by sinus bradycardia and periods of intermittent atrial fibrillation. Several genetic or acquired risk factors or pathologies can lead to SSS...
October 15, 2016: Journal of Physiology
Paola Imbrici, Concetta Altamura, Giulia Maria Camerino, Giuseppe Felice Mangiatordi, Elena Conte, Lorenzo Maggi, Raffaella Brugnoni, Kejla Musaraj, Roberta Caloiero, Domenico Alberga, Renè Massimiliano Marsano, Giulia Ricci, Gabriele Siciliano, Orazio Nicolotti, Marina Mora, Pia Bernasconi, Jean-Francois Desaphy, Renato Mantegazza, Diana Conte Camerino
Myotonia congenita is an inherited disease that is characterized by impaired muscle relaxation after contraction caused by loss-of-function mutations in the skeletal muscle ClC-1 channel. We report a novel ClC-1 mutation, T335N, that is associated with a mild phenotype in 1 patient, located in the extracellular I-J loop. The purpose of this study was to provide a solid correlation between T335N dysfunction and clinical symptoms in the affected patient as well as to offer hints for drug development. Our multidisciplinary approach includes patch-clamp electrophysiology on T335N and ClC-1 wild-type channels expressed in tsA201 cells, Western blot and quantitative PCR analyses on muscle biopsies from patient and unaffected individuals, and molecular dynamics simulations using a homology model of the ClC-1 dimer...
June 20, 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Andres Enriquez, Charles Antzelevitch, Verdah Bismah, Adrian Baranchuk
Atrial fibrillation (AF) is prevalent in cardiac channelopathies and may be the presenting feature in some patients. The pathogenesis is related to the primary ion channel dysfunction in atrial myocytes that affects atrial conduction or repolarization. The development of AF is associated with adverse outcomes, and its management is challenging in these patients. In this article we review the current information on the prevalence, risk factors, pathophysiology, and treatment of AF in specific cardiac channelopathies...
September 2016: Heart Rhythm: the Official Journal of the Heart Rhythm Society
Paola Imbrici, Antonella Liantonio, Giulia M Camerino, Michela De Bellis, Claudia Camerino, Antonietta Mele, Arcangela Giustino, Sabata Pierno, Annamaria De Luca, Domenico Tricarico, Jean-Francois Desaphy, Diana Conte
In the human genome more than 400 genes encode ion channels, which are transmembrane proteins mediating ion fluxes across membranes. Being expressed in all cell types, they are involved in almost all physiological processes, including sense perception, neurotransmission, muscle contraction, secretion, immune response, cell proliferation, and differentiation. Due to the widespread tissue distribution of ion channels and their physiological functions, mutations in genes encoding ion channel subunits, or their interacting proteins, are responsible for inherited ion channelopathies...
2016: Frontiers in Pharmacology
Mert Karakaya, Raoul Heller, Volkmar Kunde, Klaus-Peter Zimmer, Cho-Ming Chao, Peter Nürnberg, Sebahattin Cirak
Distal arthrogryposis (DA) is a feature in genetically and clinically heterogeneous groups of disorders. Mostly myopathic and neurogenic defects have been described, but many patients remain without genetic diagnosis. We are elaborating on the clinical presentation of neonatal cases with DA who carry novel mutations in the nonselective sodium leak channel (NALCN). Two patients reported herein were remarkable for central hypertonicity in addition to DA. By trio-whole exome sequencing, two undescribed de novo mutations in NALCN were revealed...
August 2016: Neuropediatrics
Heather M Byers, Christopher W Beatty, Si Houn Hahn, Sidney M Gospe
BACKGROUND: Channelopathies are a group of monogenic disorders that affect a single ion channel and can result in neurological disease. While a rare cause of epilepsy, channelopathies offer unique insight to the molecular basis of epilepsy and treatment opportunities. Calcium homeostasis is tightly regulated by a series of interacting subunits. CACNA1A encodes the principal pore-forming subunit of the voltage-gated P/Q-type calcium channel, alpha1. Patients with epileptic encephalopathy due to pathogenic variants in CACNA1A have been previously described and are challenging to treat...
July 2016: Pediatric Neurology
C N Lang, G Koren, K E Odening
Long QT syndrome (LQTS) is a rare inherited channelopathy caused mainly by different mutations in genes encoding for cardiac K(+) or Na(+) channels, but can also be caused by commonly used ion-channel-blocking and QT-prolonging drugs, thus affecting a much larger population. To develop novel diagnostic and therapeutic strategies to improve the clinical management of these patients, a thorough understanding of the pathophysiological mechanisms of arrhythmogenesis and potential pharmacological targets is needed...
July 2016: Progress in Biophysics and Molecular Biology
Roberta Gualdani, Maria Maddalena Cavalluzzi, Giovanni Lentini
Voltage-gated sodium channels (VGSC) are responsible for the selective influx of sodium ions in excitable cells. A number of physiological phenomena such as muscle contraction, pain sensation, processing of neuronal information in the brain as well as neuronal regulation of peripheral tissues rely on the activity of these channels. On the other hand, abnormal activity of VGSC are implicated in several pathological processes (e.g., cardiac arrhythmias, epilepsy, and chronic pain) which in some cases (e.g., channelopathies such as myotonias) are linked to specific gene mutations...
2016: Current Medicinal Chemistry
Sarah Weckhuysen, Elise Marsan, Virginie Lambrecq, Cécile Marchal, Mélanie Morin-Brureau, Isabelle An-Gourfinkel, Michel Baulac, Martine Fohlen, Christine Kallay Zetchi, Margitta Seeck, Pierre de la Grange, Bart Dermaut, Alfred Meurs, Pierre Thomas, Francine Chassoux, Eric Leguern, Fabienne Picard, Stéphanie Baulac
OBJECTIVE: The discovery of mutations in DEPDC5 in familial focal epilepsies has introduced a novel pathomechanism to a field so far dominated by ion channelopathies. DEPDC5 is part of a complex named GAP activity toward RAGs (GATOR) complex 1 (GATOR1), together with the proteins NPRL2 and NPRL3, and acts to inhibit the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) pathway. GATOR1 is in turn inhibited by the GATOR2 complex. The mTORC1 pathway is a major signaling cascade regulating cell growth, proliferation, and migration...
June 2016: Epilepsia
Eszter Szepesváry, Juan Pablo Kaski
Cardiac channelopathies are linked to an increased risk of ventricular arrhythmia and sudden death. This article reviews the clinical characteristics and genetic basis of common cardiac ion-channel diseases, highlights some genotype-phenotype correlations, and summarizes genetic testing for inheritable cardiac channelopathies.
May 2016: British Journal of Hospital Medicine
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