DOCSLIB.ORG

Mutations of Voltage-Gated Ionic Channels and Risk of Severe Cardiac Arrhythmias

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Mutations of Voltage-Gated Ionic Channels and Risk of Severe Cardiac Arrhythmias Acta Cardiol Sin 2019;35:99-110 Review Article doi: 10.6515/ACS.201903_35(2).20181028A Mutations of Voltage-Gated Ionic Channels and Risk of Severe Cardiac Arrhythmias Amir Dehghani-Samani,1 Samin Madreseh-Ghahfarokhi2 and Azam Dehghani-Samani3 Background: Arrhythmias as important malfunctions of heart are known as abnormal rhythm of heart. Several causes can make arrhythmias and most of them are related to generation and/or conduction of action potential in heart. Action potential in myocytes results from the sequential opening and closing of ion channel proteins that span the plasma membrane of individual myocytes. Action potential’s conduction through the heart is depended on electrical coupling between myocytes, which is mediated by gap junctions. Generation and conduction of action potentials are related to perfect action of ionic channels in heart. Objectives: This novel review comprehensively addressed the ionic mechanisms of the arrhythmogenic mutations in cardiac voltage-gated ionic channels including: CACNA1C, CACNA1D, KCNA5, KCND2, KCND3, KCNE1, KCNE2, KCNE5, KCNH2, KCNJ2, KCNJ5, KCNQ1, SCN4A, SCN5A, SCN1B, SCN2B, SCN3B and SCN4B. Methods: Current study, for the first time, review and discuses about relation between cardiac arrhythmias and whole of important voltage gated ionic channels from different families, altogether and at the same time. Results: This review clears that mutations in voltage-gated ionic channels play important roles in generation of severe cardiac arrhythmias, and among them it is looked that mutations in voltage-gated potassium channels are more important. Conclusions: Most of induced arrhythmias due to voltage-gated ionic channels mutations result in action potentials prolongation and long QT syndromes. Study on ionic channel regulators can be considered as a subject for future research. Key Words: Arrhythmia · Ion channel · Ionic current INTRODUCTION atria no longer function as primer pumps for the ventri- cles.1 Related symptoms to cardiac arrhythmias are in- Cardiac arrhythmias, as important kinds of heart cluding: shortness of breath, weakness, lightheaded- malfunctions, are occurring due to abnormal rhythm of ness, dizziness and occasionally, chest pain in mild types the heart. For instance, sometimes the beat of the atria of arrhythmias, and fainting, loss of conscious, syncope is not coordinated with the beat of the ventricles, so the and finally death in severe types of arrhythmias. The causes of the cardiac arrhythmias are usually related to generation and/or conduction of action potentials (APs) Received: April 4, 2018 Accepted: October 28, 2018 in cardiac tissues, which are sharply related to perfect 1Department of Clinical Sciences, Faculty of Veterinary Medicine, action of ionic channels in heart.1 Shahrekord University, Shahrekord; 2Department of Clinical Sciences, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad; 3Faculty of Veterinary Medicine, Shahrekord University, Shahrekord, Iran. DIFFERENT TYPES OF ARRHYTHMIA Corresponding author: Dr. Amir Dehghani Samani, Department of Clinical Sciences, Faculty of Veterinary Medicine, Shahrekord University, Shahrekord, Iran. Tel: +98-3814424427; Fax: +98-3814424427; E-mail: According to the specific cause and character, car- [email protected] diac arrhythmias can divide to different groups. In one 99 Acta Cardiol Sin 2019;35:99-110 Amir Dehghani-Samani et al. of the best divisions, they are divided into eight differ- sub-divisions and different characteristics of each type ent categories.1 Table 1 shows the causes, mechanisms, of arrhythmias. Table 1. Different groups of arrhythmias and their characteristics Characteristics, electrocardiogram Type of arrhythmia Subtypes Common cause (ECG), etc. Abnormal sinus rhythms1 Tachycardia1 Increased body temperature, Heart rate more than 100 beats/ stimulation of the heart by min, ECG: normal, except heart rate.1 sympathetic nerves, toxic conditions, etc.1 Bradycardia1 Large and strong heart, vagal Heart rate less than 60 beats/min, stimulation, etc.1 ECG: normal, except heart rate.1 Sinus arrhythmia1 Alter in strength of the sympathetic Range of increasing/decreasing in and parasympathetic signals to sinus heart rate during the stimulation is node, etc.1 more than normal range.1 Block of heart signals1 Sinoatrial block1 Impulse from sinus node is blocked Sudden cessation of P waves in ECG, before it enters to atrial muscle, etc.1 with resultant standstill of the atria.1 Atrioventricular block1 Decrease the rate of impulse Prolonged P-R or P-Q Interval (First conduction in atrioventricular bundle, degree), P wave with no QRS-T wave etc.1 (2nd degree), Dissociated P wave from QRS-T complexes (3rd degree).1 Incomplete Block impulse conduction in the Replicated increasing/decreasing in intraventri-cular block1 peripheral ventricular Purkinje system, height of QRS wave.1 etc.1 Premature contractions1 Premature atrial Mostly result from ectopic foci in P wave occurs soon, P-R interval is contractions1 heart due to local areas of ischemia; shortened.1 Atrioventricular nodal small calcified plaques and toxic P wave is missing; instead P wave is contractions1 irritation of the Atrioventriclar node, superimposed onto QRS-T complex.1 Premature ventricular Purkinje system or myocardium caused Prolonged QRS with high voltage, T contractions1 by infection, drugs, nicotine, or wave has electrical potential polarity caffeine, etc.1 exactly opposite to QRS.1 Paroxysmal tachycardia1 Atrial paroxysmal Mostly caused by re-entrant circus Inverted P wave is seen before tachycardia1 movement feedback pathways that each QRS-T complex.1 Ventricular paroxysmal set up local repeated self-re-excitation Series of ventricular premature beats tachycardia1 and this focus becomes the pacemaker occurring one after another without of the heart, etc.1 any normal beats interspersed.1 Ventricular fibrillation1 Results from cardiac impulses that have gone berserk within ECG is bizarre and ordinarily shows the ventricular muscle mass, stimulating first one portion of no tendency toward a regular the ventricular muscle, then another portion, then another, rhythm of any type.1 and eventually feeding back onto itself to re-excite the same ventricular muscle over and over, never stopping, etc.1 Atrial fibrillation1 Mechanism of atrial fibrillation is identical to that of Numerous small depolarization ventricular fibrillation, except that the process occurs only in waves exist. P waves are weak; the atrial muscle mass, etc.1 conversely, QRS-T complexes are normal.1 Atrial flutter1 Caused by circus movements in the atria. It causes a rapid rate P waves are strong, QRS-T complex of contraction of the atria, usually between 200 and 350 beats follows an atrial P wave only once per minute, etc.1 for every two to three beats of the atria.1 Cardiac arrest1 Results from cessation of all electrical control signals in the Stop of waves.1 heart, etc.1 Acta Cardiol Sin 2019;35:99-110 100 Genetic Disorders and Risk of Cardiac Arrhythmias NORMAL GENERATION OF ACTION POTENTIALS 1showsthedifferentphasesofAP’sgenerationinmyo- (APs) cytes schematically. Several factor regulate the genera- tion and conduction of APs including:1 changes in the The best introduced mechanism for AP in cardiac properties and/or in the functional expression of ionic cells, which is explained by scientists, indicates that AP channels, which are resulted from inherited mutations in myocytes results from the sequential opening and in the genes encoding these channels,1 or from cardiac closing of ion channels span in plasma membrane of in- diseases,1 which can change the AP’s waveforms, synch- dividual myocytes. Also differences in the expression and ronization, and/or propagation, thereby predisposing properties of these channels result in heterogeneities in the heart to potentially life-threatening arrhythmias.2 AP wave. Action potential’s conduction through the heart depends on electrical coupling between myocytes, which is mediated by gap junctions.1 The cardiac AP in VOLTAGE-GATED IONIC CHANNELS (VGICs) humans has five different phases (from 0 to 4). Depolar- ization from the pacemaker cells in Sino-Atrial node VGICs are an important and specific class of trans- brings the membrane potential to the threshold, open- membrane channels.1 The first identified VGIC that was ing the voltage-activated sodium channels, then the re- voltage-gated sodium channel or (VGSC) was isolated 3 sulting sodium current (INa) produces a positive feed- and purified from the eel electroplax. The first volt- back loop that causes further sodium channels to open age-gated potassium channel’s sequence was deduced (phase0).Innextstepearlyrapidrepolarizationresults from the Shaker mutant of Drosophila melanogaster.3 from the activation of the fast and slow transient out- Some functional VGICs are made up a protein with four ward potassium currents, Ito,f and Ito,s, and it is responsi- different subunits like voltage gated potassium chan- ble for phase 1 of the AP’s generation. This is followed nels (VGPCs), or one protein with four homologous do- by a prolonged plateau resulting from a balance between mains like VGSCs and voltage gated calcium channels the inward currents mediated by the L-type voltage- (VGCCs). Each one of the domains or subunits has six gated calcium channel (ICa,L) and sodium-calcium ex- trans-membrane segments (S1-6) and a pore loop; the changer (INCX),andtheoutwardcurrentsmediatedby S5, S6 and the pore loop were found to be responsible the delayed
Load more

Recommended publications
  • Paramyotonia Congenita
    Paramyotonia congenita Description Paramyotonia congenita is a disorder that affects muscles used for movement (skeletal muscles). Beginning in infancy or early childhood, people with this condition experience bouts of sustained muscle tensing (myotonia) that prevent muscles from relaxing normally. Myotonia causes muscle stiffness that typically appears after exercise and can be induced by muscle cooling. This stiffness chiefly affects muscles in the face, neck, arms, and hands, although it can also affect muscles used for breathing and muscles in the lower body. Unlike many other forms of myotonia, the muscle stiffness associated with paramyotonia congenita tends to worsen with repeated movements. Most people—even those without muscle disease—feel that their muscles do not work as well when they are cold. This effect is dramatic in people with paramyotonia congenita. Exposure to cold initially causes muscle stiffness in these individuals, and prolonged cold exposure leads to temporary episodes of mild to severe muscle weakness that may last for several hours at a time. Some older people with paramyotonia congenita develop permanent muscle weakness that can be disabling. Frequency Paramyotonia congenita is an uncommon disorder; it is estimated to affect fewer than 1 in 100,000 people. Causes Mutations in the SCN4A gene cause paramyotonia congenita. This gene provides instructions for making a protein that is critical for the normal function of skeletal muscle cells. For the body to move normally, skeletal muscles must tense (contract) and relax in a coordinated way. Muscle contractions are triggered by the flow of positively charged atoms (ions), including sodium, into skeletal muscle cells. The SCN4A protein forms channels that control the flow of sodium ions into these cells.
    [Show full text]
  • Update on the Implication of Potassium Channels in Autism: K+ Channelautism Spectrum Disorder
    REVIEW ARTICLE published: 02 March 2015 doi: 10.3389/fncel.2015.00034 Update on the implication of potassium channels in autism: K+ channelautism spectrum disorder Luca Guglielmi 1*, Ilenio Servettini 1, Martino Caramia 2 , Luigi Catacuzzeno 2 , Fabio Franciolini 2 , Maria Cristina D’Adamo1 and Mauro Pessia1* 1 Section of Physiology and Biochemistry, Department of Experimental Medicine, University of Perugia School of Medicine, Perugia, Italy 2 Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia, Italy Edited by: Autism spectrum disorders (ASDs) are characterized by impaired ability to properly Tycho M. Hoogland, Netherlands implement environmental stimuli that are essential to achieve a state of social and Institute for Neuroscience, Netherlands cultural exchange. Indeed, the main features of ASD are impairments of interpersonal relationships, verbal and non-verbal communication and restricted and repetitive behaviors. Reviewed by: Noritaka Ichinohe, National Institute of These aspects are often accompanied by several comorbidities such as motor delay, Neuroscience – National Center of praxis impairment, gait abnormalities, insomnia, and above all epilepsy. Genetic analyses Neurology and Psychiatry, Japan of autistic individuals uncovered deleterious mutations in several K+ channel types Mohamed Jaber, University of Poitiers, France strengthening the notion that their intrinsic dysfunction may play a central etiologic role in ASD. However, indirect implication of K+ channels in ASD has been also reported. *Correspondence: + Luca Guglielmi and Mauro Pessia, For instance, loss of fragile X mental retardation protein (FMRP) results in K channels Section of Physiology and deregulation, network dysfunction and ASD-like cognitive and behavioral symptoms. This Biochemistry, Department of review provides an update on direct and indirect implications of K+ channels in ASDs.
    [Show full text]
  • The Mineralocorticoid Receptor Leads to Increased Expression of EGFR
    www.nature.com/scientificreports OPEN The mineralocorticoid receptor leads to increased expression of EGFR and T‑type calcium channels that support HL‑1 cell hypertrophy Katharina Stroedecke1,2, Sandra Meinel1,2, Fritz Markwardt1, Udo Kloeckner1, Nicole Straetz1, Katja Quarch1, Barbara Schreier1, Michael Kopf1, Michael Gekle1 & Claudia Grossmann1* The EGF receptor (EGFR) has been extensively studied in tumor biology and recently a role in cardiovascular pathophysiology was suggested. The mineralocorticoid receptor (MR) is an important efector of the renin–angiotensin–aldosterone‑system and elicits pathophysiological efects in the cardiovascular system; however, the underlying molecular mechanisms are unclear. Our aim was to investigate the importance of EGFR for MR‑mediated cardiovascular pathophysiology because MR is known to induce EGFR expression. We identifed a SNP within the EGFR promoter that modulates MR‑induced EGFR expression. In RNA‑sequencing and qPCR experiments in heart tissue of EGFR KO and WT mice, changes in EGFR abundance led to diferential expression of cardiac ion channels, especially of the T‑type calcium channel CACNA1H. Accordingly, CACNA1H expression was increased in WT mice after in vivo MR activation by aldosterone but not in respective EGFR KO mice. Aldosterone‑ and EGF‑responsiveness of CACNA1H expression was confrmed in HL‑1 cells by Western blot and by measuring peak current density of T‑type calcium channels. Aldosterone‑induced CACNA1H protein expression could be abrogated by the EGFR inhibitor AG1478. Furthermore, inhibition of T‑type calcium channels with mibefradil or ML218 reduced diameter, volume and BNP levels in HL‑1 cells. In conclusion the MR regulates EGFR and CACNA1H expression, which has an efect on HL‑1 cell diameter, and the extent of this regulation seems to depend on the SNP‑216 (G/T) genotype.
    [Show full text]
  • Towards Mutation-Specific Precision Medicine in Atypical Clinical
    International Journal of Molecular Sciences Review Towards Mutation-Specific Precision Medicine in Atypical Clinical Phenotypes of Inherited Arrhythmia Syndromes Tadashi Nakajima * , Shuntaro Tamura, Masahiko Kurabayashi and Yoshiaki Kaneko Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, Maebashi 371-8511, Gunma, Japan; [email protected] (S.T.); [email protected] (M.K.); [email protected] (Y.K.) * Correspondence: [email protected]; Tel.: +81-27-220-8145; Fax: +81-27-220-8158 Abstract: Most causal genes for inherited arrhythmia syndromes (IASs) encode cardiac ion channel- related proteins. Genotype-phenotype studies and functional analyses of mutant genes, using heterol- ogous expression systems and animal models, have revealed the pathophysiology of IASs and enabled, in part, the establishment of causal gene-specific precision medicine. Additionally, the utilization of induced pluripotent stem cell (iPSC) technology have provided further insights into the patho- physiology of IASs and novel promising therapeutic strategies, especially in long QT syndrome. It is now known that there are atypical clinical phenotypes of IASs associated with specific mutations that have unique electrophysiological properties, which raises a possibility of mutation-specific precision medicine. In particular, patients with Brugada syndrome harboring an SCN5A R1632C mutation exhibit exercise-induced cardiac events, which may be caused by a marked activity-dependent loss of R1632C-Nav1.5 availability due to a marked delay of recovery from inactivation. This suggests that the use of isoproterenol should be avoided. Conversely, the efficacy of β-blocker needs to be examined. Patients harboring a KCND3 V392I mutation exhibit both cardiac (early repolarization syndrome and Citation: Nakajima, T.; Tamura, S.; paroxysmal atrial fibrillation) and cerebral (epilepsy) phenotypes, which may be associated with a Kurabayashi, M.; Kaneko, Y.
    [Show full text]
  • Examining the Regulation of Kv7 K+ Channels in Airway Smooth Muscle Cells and Their Potential As Novel Therapeutic Targets for the Treatment of Asthma
    Loyola University Chicago Loyola eCommons Dissertations Theses and Dissertations 2017 Examining the Regulation of Kv7 K+ Channels in Airway Smooth Muscle Cells and Their Potential as Novel Therapeutic Targets for the Treatment of Asthma Jennifer Haick Loyola University Chicago Follow this and additional works at: https://ecommons.luc.edu/luc_diss Part of the Pharmacology Commons Recommended Citation Haick, Jennifer, "Examining the Regulation of Kv7 K+ Channels in Airway Smooth Muscle Cells and Their Potential as Novel Therapeutic Targets for the Treatment of Asthma" (2017). Dissertations. 2588. https://ecommons.luc.edu/luc_diss/2588 This Dissertation is brought to you for free and open access by the Theses and Dissertations at Loyola eCommons. It has been accepted for inclusion in Dissertations by an authorized administrator of Loyola eCommons. For more information, please contact [email protected]. This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License. Copyright © 2017 Jennifer Haick LOYOLA UNIVERSITY CHICAGO EXAMINING THE REGULATION OF Kv7 K+ CHANNELS IN AIRWAY SMOOTH MUSCLE CELLS AND THEIR POTENTIAL AS NOVEL THERAPEUTIC TARGETS FOR THE TREATMENT OF ASTHMA A DISSERTATION SUBMITTED TO THE FACULTY OF THE GRADUATE SCHOOL IN CANDIDACY FOR THE DEGREE OF DOCTOR OF PHILOSOPHY PROGRAM IN MOLECULAR PHARMACOLOGY AND THERAPEUTICS BY JENNIFER HAICK CHICAGO, IL MAY 2017 ACKNOWLEDGEMENTS I would like to take a moment to thank all of the people who have helped and supported me these past years while I have been working towards my Ph.D. First and foremost, I would like to thank Dr. Kenneth Byron for accepting me into his lab and for his mentorship these past years.
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • Emerging Roles for Multifunctional Ion Channel Auxiliary Subunits in Cancer T ⁎ Alexander S
    Cell Calcium 80 (2019) 125–140 Contents lists available at ScienceDirect Cell Calcium journal homepage: www.elsevier.com/locate/ceca Emerging roles for multifunctional ion channel auxiliary subunits in cancer T ⁎ Alexander S. Hawortha,b, William J. Brackenburya,b, a Department of Biology, University of York, Heslington, York, YO10 5DD, UK b York Biomedical Research Institute, University of York, Heslington, York, YO10 5DD, UK ARTICLE INFO ABSTRACT Keywords: Several superfamilies of plasma membrane channels which regulate transmembrane ion flux have also been Auxiliary subunit shown to regulate a multitude of cellular processes, including proliferation and migration. Ion channels are Cancer typically multimeric complexes consisting of conducting subunits and auxiliary, non-conducting subunits. Calcium channel Auxiliary subunits modulate the function of conducting subunits and have putative non-conducting roles, further Chloride channel expanding the repertoire of cellular processes governed by ion channel complexes to processes such as trans- Potassium channel cellular adhesion and gene transcription. Given this expansive influence of ion channels on cellular behaviour it Sodium channel is perhaps no surprise that aberrant ion channel expression is a common occurrence in cancer. This review will − focus on the conducting and non-conducting roles of the auxiliary subunits of various Ca2+,K+,Na+ and Cl channels and the burgeoning evidence linking such auxiliary subunits to cancer. Several subunits are upregu- lated (e.g. Cavβ,Cavγ) and downregulated (e.g. Kvβ) in cancer, while other subunits have been functionally implicated as oncogenes (e.g. Navβ1,Cavα2δ1) and tumour suppressor genes (e.g. CLCA2, KCNE2, BKγ1) based on in vivo studies. The strengthening link between ion channel auxiliary subunits and cancer has exposed these subunits as potential biomarkers and therapeutic targets.
    [Show full text]
  • KCND3 Potassium Channel Gene Variant Confers Susceptibility to Electrocardiographic Early Repolarization Pattern
    KCND3 potassium channel gene variant confers susceptibility to electrocardiographic early repolarization pattern Alexander Teumer, … , Elijah R. Behr, Wibke Reinhard JCI Insight. 2019. https://doi.org/10.1172/jci.insight.131156. Clinical Medicine In-Press Preview Cardiology Genetics Graphical abstract Find the latest version: https://jci.me/131156/pdf 1 KCND3 potassium channel gene variant confers susceptibility to 2 electrocardiographic early repolarization pattern 3 Alexander Teumer1,2*, Teresa Trenkwalder3*, Thorsten Kessler3, Yalda Jamshidi4, Marten E. van den 4 Berg5, Bernhard Kaess6, Christopher P. Nelson7,8, Rachel Bastiaenen9, Marzia De Bortoli10, 5 Alessandra Rossini10, Isabel Deisenhofer3, Klaus Stark11, Solmaz Assa12, Peter S. Braund7,8, Claudia 6 Cabrera13,14,15, Anna F. Dominiczak16, Martin Gögele10, Leanne M. Hall7,8, M. Arfan Ikram5, Maryam 7 Kavousi5, Karl J. Lackner17,18, Lifelines Cohort Study19, Christian Müller20, Thomas Münzel18,21, 8 Matthias Nauck2,22, Sandosh Padmanabhan16, Norbert Pfeiffer23, Tim D. Spector24, Andre G. 9 Uitterlinden5, Niek Verweij12, Uwe Völker2,25, Helen R. Warren13,14, Mobeen Zafar12, Stephan B. 10 Felix2,26, Jan A. Kors27, Harold Snieder28, Patricia B. Munroe13,14, Cristian Pattaro10, Christian 11 Fuchsberger10, Georg Schmidt29,30, Ilja M. Nolte28, Heribert Schunkert3,30, Peter Pramstaller10, Philipp 12 S. Wild31, Pim van der Harst12, Bruno H. Stricker5, Renate B. Schnabel20, Nilesh J. Samani7,8, 13 Christian Hengstenberg32, Marcus Dörr2,26, Elijah R. Behr33, Wibke Reinhard3 14 15 16 1 Institute
    [Show full text]
  • Variants in the KCNE1 Or KCNE3 Gene and Risk of Ménière’S Disease: a Meta-Analysis
    Journal of Vestibular Research 25 (2015) 211–218 211 DOI 10.3233/VES-160569 IOS Press Variants in the KCNE1 or KCNE3 gene and risk of Ménière’s disease: A meta-analysis Yuan-Jun Li, Zhan-Guo Jin and Xian-Rong Xu∗ The Center of Clinical Aviation Medicine, General Hospital of Air Force, Beijing, China Received 1 August 2015 Accepted 8 December 2015 Abstract. BACKGROUND: Ménière’s disease (MD) is defined as an idiopathic disorder of the inner ear characterized by the triad of tinnitus, vertigo, and sensorineural hearing loss. Although many studies have evaluated the association between variants in the KCNE1 or KCNE3 gene and MD risk, debates still exist. OBJECTIVE: Our aim is to evaluate the association between KCNE gene variants, including KCNE1 rs1805127 and KCNE3 rs2270676, and the risk of MD by a systematic review. METHODS: We searched the literature in PubMed, SCOPUS and EMBASE through May 2015. We calculated pooled odds ra- tios (OR) and 95% confidence intervals (CIs) using a fixed-effects model or a random-effects model for the risk to MD associated with different KCNE gene variants. The heterogeneity assumption decided the effect model. RESULTS: A total of three relevant studies, with 302 MD cases and 515 controls, were included in this meta-analysis. The results indicated that neither the KCNE1 rs1805127 variant (for G vs. A: OR = 0.724, 95%CI 0.320, 1.638, P = 0.438), nor the KCNE3 rs2270676 variant (for T vs. C: OR = 0.714, 95%CI 0.327, 1.559, P = 0.398) was associated with MD risk.
    [Show full text]
  • Investigation of Candidate Genes and Mechanisms Underlying Obesity
    Prashanth et al. BMC Endocrine Disorders (2021) 21:80 https://doi.org/10.1186/s12902-021-00718-5 RESEARCH ARTICLE Open Access Investigation of candidate genes and mechanisms underlying obesity associated type 2 diabetes mellitus using bioinformatics analysis and screening of small drug molecules G. Prashanth1 , Basavaraj Vastrad2 , Anandkumar Tengli3 , Chanabasayya Vastrad4* and Iranna Kotturshetti5 Abstract Background: Obesity associated type 2 diabetes mellitus is a metabolic disorder ; however, the etiology of obesity associated type 2 diabetes mellitus remains largely unknown. There is an urgent need to further broaden the understanding of the molecular mechanism associated in obesity associated type 2 diabetes mellitus. Methods: To screen the differentially expressed genes (DEGs) that might play essential roles in obesity associated type 2 diabetes mellitus, the publicly available expression profiling by high throughput sequencing data (GSE143319) was downloaded and screened for DEGs. Then, Gene Ontology (GO) and REACTOME pathway enrichment analysis were performed. The protein - protein interaction network, miRNA - target genes regulatory network and TF-target gene regulatory network were constructed and analyzed for identification of hub and target genes. The hub genes were validated by receiver operating characteristic (ROC) curve analysis and RT- PCR analysis. Finally, a molecular docking study was performed on over expressed proteins to predict the target small drug molecules. Results: A total of 820 DEGs were identified between
    [Show full text]
  • Control Qpatch Htx Multi-Hole
    41577_Poster 170x110.qxd:Poster 170x110 07/04/10 8:52 Side 1 SOPHION BIOSCIENCE A/S SOPHION BIOSCIENCE, INC. SOPHION JAPAN Baltorpvej 154 675 US Highway One 1716-6, Shimmachi ENHANCING THROUGHPUT WITH MULTIPLE DK-2750 Ballerup North Brunswick, NJ 08902 Takasaki-shi, Gumma 370-1301 DENMARK USA JAPAN [email protected] Phone: +1 732 745 0221 Phone: +81 274 50 8388 CELL LINES PER WELL WITH THE QPATCH HTX www.sophion.com www.sophion.com www.sophion.com HERVØR LYKKE OLSEN l DORTHE NIELSEN l MORTEN SUNESEN QPATCH HTX MULTI-HOLE: TEMPORAL CURRENT QPATCH HTX MULTI-HOLE: PHARMACOLOGICAL SEPARATION BASED ON DISCRETE RECORDING SEPARATION BASED ON ION CHANNEL INHIBITORS TIME WINDOWS KvLQT1/minK (KCNQ1/KCNE1) INTRODUCTION Kv1.5 (KCNA5) ABRaw traces (A) and Hill plot (B) for XE991. ABC hERG and Nav1.5 blocked by E-4031 and The QPatch HTX automated patch clamp technology was developed to 1) increase throughput in ion channel drug TTX, respectively. screening by parallel operation of 48 multi-hole patch clamp sites, each comprising 10 individual patch clamp holes, in a single measurements site on a QPlate X, and 2) diminish problems with low-expressing cell lines. Thus, parallel recording from 10 cells represents a 10-fold signal amplification, and it increases the success rate at each site substantially. To further increase throughput we explored the possibility of simultaneous recording of a number of ion channel currents. IC50 (μM) XE991 Two or three cell lines, each expressing a specific ion channel, were applied at each site simultaneously. The ion channel Measured Literature currents were separated temporally or pharmacologically by proper choices of voltage protocols or ion channel KvLQT1 3.5±1.0 (n=12) 1-6 (Ref.
    [Show full text]
  • Expression Profiling of Ion Channel Genes Predicts Clinical Outcome in Breast Cancer
    UCSF UC San Francisco Previously Published Works Title Expression profiling of ion channel genes predicts clinical outcome in breast cancer Permalink https://escholarship.org/uc/item/1zq9j4nw Journal Molecular Cancer, 12(1) ISSN 1476-4598 Authors Ko, Jae-Hong Ko, Eun A Gu, Wanjun et al. Publication Date 2013-09-22 DOI http://dx.doi.org/10.1186/1476-4598-12-106 Peer reviewed eScholarship.org Powered by the California Digital Library University of California Ko et al. Molecular Cancer 2013, 12:106 http://www.molecular-cancer.com/content/12/1/106 RESEARCH Open Access Expression profiling of ion channel genes predicts clinical outcome in breast cancer Jae-Hong Ko1, Eun A Ko2, Wanjun Gu3, Inja Lim1, Hyoweon Bang1* and Tong Zhou4,5* Abstract Background: Ion channels play a critical role in a wide variety of biological processes, including the development of human cancer. However, the overall impact of ion channels on tumorigenicity in breast cancer remains controversial. Methods: We conduct microarray meta-analysis on 280 ion channel genes. We identify candidate ion channels that are implicated in breast cancer based on gene expression profiling. We test the relationship between the expression of ion channel genes and p53 mutation status, ER status, and histological tumor grade in the discovery cohort. A molecular signature consisting of ion channel genes (IC30) is identified by Spearman’s rank correlation test conducted between tumor grade and gene expression. A risk scoring system is developed based on IC30. We test the prognostic power of IC30 in the discovery and seven validation cohorts by both Cox proportional hazard regression and log-rank test.
    [Show full text]