DOCSLIB.ORG

Mutations in the Chloride Channel Gene CLCNKB As a Cause of Classic Bartter Syndrome

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Mutations in the Chloride Channel Gene CLCNKB As a Cause of Classic Bartter Syndrome J Am Soc Nephrol 11: 1449–1459, 2000 Mutations in the Chloride Channel Gene CLCNKB as a Cause of Classic Bartter Syndrome MARTIN KONRAD,* MARTIN VOLLMER,† HENNY H. LEMMINK,‡ LAMBERTUS P. W. J. VAN DEN HEUVEL,‡ NIKOLA JECK,* ROSA VARGAS-POUSSOU,§ ALICIA LAKINGS,ʈ RAINER RUF,† GEORGES DESCHENES,ˆ ¶ CORINNE ANTIGNAC,§ LISA GUAY-WOODFORD,ʈ NINE V. A. M. KNOERS,‡ HANNSJORG¨ W. SEYBERTH,* DELPHINE FELDMANN,¶ and FRIEDHELM HILDEBRANDT† *Department of Pediatrics, Philipps University, Marburg, Germany; †Department of Pediatrics, Albert Ludwigs University of Freiburg, Germany; ‡Departments of Pediatrics and Human Genetics, University Hospital Nijmegen, The Netherlands; §Institut National de la Sante´et de la Recherche Me´dicale U423, Necker Hospital, University of Paris, France; ʈDepartments of Medicine and Pediatrics, University of Alabama at Birmingham, Alabama; ¶Departments of Biochemistry and Pediatric Nephrology, Armand-Trousseau Hospital, Paris, France. Abstract. Inherited hypokalemic renal tubulopathies are differ- ROMK (KCNJ1). Recently, mutations in a basolateral chloride entiated into at least three clinical subtypes: (1) the Gitelman channel CLC-Kb (CLCNKB) have been described in a subset variant of Bartter syndrome (GS); (2) hyperprostaglandin E of patients with a Bartter-like phenotype typically lacking syndrome, the antenatal variant of Bartter syndrome (HPS/ nephrocalcinosis. In this study, the screening for CLCNKB aBS); and (3) the classic Bartter syndrome (cBS). Hypokale- mutations showed 20 different mutations in the affected mic metabolic alkalosis and renal salt wasting are the common children from 30 families. The clinical characterization re- characteristics of all three subtypes. Hypocalciuria and hypo- vealed a highly variable phenotype ranging from episodes of magnesemia are specific clinical features of Gitelman syn- severe volume depletion and hypokalemia during the neo- drome, while HPS/aBS is a life-threatening disorder of the natal period to almost asymptomatic patients diagnosed newborn with polyhydramnios, premature delivery, hyposthe- during adolescence. This study adds 16 novel mutations to nuria, and nephrocalcinosis. The Gitelman variant is uniformly the nine already described, providing further evidence that caused by mutations in the gene for the thiazide-sensitive mutations in the gene for the basolateral chloride channel NaCl-cotransporter NCCT (SLC12A3) of the distal tubule, CLC-Kb are the molecular basis of classic Bartter syn- while HPS/aBS is caused by mutations in the gene for either drome. Interestingly, the phenotype elicited by CLCNKB the furosemide-sensitive NaK-2Cl-cotransporter NKCC2 mutations occasionally includes HPS/aBS, as well as a (SLC12A1) or the inwardly rectifying potassium channel Gitelman-like phenotype. Inherited hypokalemic tubulopathies have previously been defects and extensive pathophysiologic studies have allowed a summarized under the term Bartter syndrome (BS). All disease more stringent molecular genetic classification. However, the variants follow autosomal recessive inheritance and share the correlation between molecular genetic defects and the clinical following characteristic clinical features: renal salt wasting, phenotype has not been clearly delineated as yet. From a hypokalemic metabolic alkalosis, normotensive hyperrenine- clinical perspective, the classification into three different vari- mic hyperaldosteronism, and hyperplasia of the juxtaglomeru- ants seems justified (1,2): lar apparatus. Recent identification of the primary genetic 1. In Gitelman syndrome (GS), the hypocalciuric-hypomag- nesemic variant (3), patients are often asymptomatic with the exception of transient muscular weakness, carpopedal Received October 18, 1999. Accepted January 18, 2000. Dr. Martin Konrad and Dr. Martin Vollmer contributed equally to this work. spasms, tetanic episodes, and abdominal pain. Therefore, Dr. Daniel G. Bichet served as Guest Editor and supervised the review and diagnosis is made as a rule after the age of 6 yr. In contrast final disposition of this manuscript. to the other variants, there is marked hypocalciuria and Correspondence to Dr. Hannsjo¨rg W. Seyberth, Department of Pediatrics, hypomagnesemia. Philipps University, Deutschhausstrasse 12, D-35037 Marburg, Germany. 2. Hyperprostaglandin E syndrome (HPS), also known as an- Phone: ϩ49 6421 2866226; Fax: ϩ49 6421 2868956; E-mail: seyberth@ mailer.uni-marburg.de tenatal Bartter syndrome (aBS) (1,2,4,5), is the most severe 1046-6673/1108-1449 form and leads to polyhydramnios and premature birth due Journal of the American Society of Nephrology to excessive polyuria in utero. Often there is a life-threat- Copyright © 2000 by the American Society of Nephrology ening clinical course in the perinatal period with severe salt 1450 Journal of the American Society of Nephrology J Am Soc Nephrol 11: 1449–1459, 2000 and water loss, hypokalemic alkalosis, and systemic mani- ROMK. Clinically, the cohort consisted of patients with GS festations such as fever, vomiting, diarrhea, and failure to (n ϭ 5), HPS/aBS (n ϭ 7), and cBS (n ϭ 38). In 36 patients thrive. Marked hypercalciuria and the development of from 30 families, 20 different mutations in CLCNKB were nephrocalcinosis ensue often within several weeks. Gener- detected, 16 of which are novel. These patients were carefully alized symptoms have been attributed to enhanced systemic reanalyzed clinically. We found that these patients presented prostaglandin formation, and treatment with indomethacin, with a highly variable phenotype, ranging from a severe peri- an inhibitor of prostaglandin synthesis, is the most effective natal course to patients who were almost symptom-free and therapeutic option (5). were diagnosed only by accidental detection of hypokalemia 3. Classic Bartter syndrome (cBS) presents with sequelae of with the majority fulfilling the criteria of cBS. A novel non- pronounced hypokalemia and marked salt loss resulting in homologous recombination event in the CLCNKB gene was muscle weakness and volume contraction during the first detected. years of life. Nephrocalcinosis is an uncommon finding, and investigation of renal concentrating ability is impaired to a Materials and Methods lesser extent than in HPS/aBS (2). Patients We analyzed by mutational analysis 50 patients from 43 families Recently, four distinct primary genetic defects have been diagnosed as having either GS (n ϭ 5), HPS/aBS (n ϭ 7), or cBS (n ϭ elucidated for different variants of BS: 38), in whom no linkage to or mutations in SLC12A3, SLC12A1, and KCNJ1 was detected in previous studies (7,10,11,14,15,17). Diagno- 1. GS (MIM 263800) is caused by mutations in the NaCl sis of GS and HPS/aBS was made following the criteria of Bettinelli cotransporter gene (SLC12A3), encoding a protein located et al. (18) and Seyberth et al. (4,5), respectively. Patients were in the apical membrane of the distal convoluted tubule, considered as having cBS when they presented with hypokalemic which is known to be inhibited by thiazides (6,7). There- alkalosis, renal salt wasting without antenatal manifestation, and no fore, the symptoms of GS mimic chronic administration of major disturbance of serum calcium or magnesium. This study was thiazides (8). In contrast to GS, HPS/aBS was found to be approved by the local ethics committee, and informed consent was caused by at least two different genes: obtained from the patients and/or their parents. 2. Mutations in the furosemide-sensitive luminal Na-K-2Cl cotransporter (SLC12A1), which is expressed in the thick Genotype Analysis and Haplotype Construction ascending limb of Henle’s loop, cause the genetic variant of Genomic DNA of all affected individuals and available family BS type 1 (MIM 600839) and lead to the clinical phenotype members was extracted from whole blood by standard methods (19) of HPS/aBS (9–11). This is in keeping with the observation or after Epstein-Barr virus transformation of peripheral blood lym- that there is an impaired response to furosemide in HPS/ phocytes (20). Haplotype analysis was performed as described previ- ously (14), using the following markers, which were linked to the aBS patients and that the clinical phenotype of HPS/aBS CLCNKA/CLCNKB loci: D1S2826, D1S2672, D1S2644, D1S507, and mimics the sequelae of chronic furosemide treatment (12). D1S436 (21). 3. Mutations in the gene for the inwardly rectifying potassium Microsatellite polymorphisms were amplified as described previ- channel ROMK (KCNJ1) cause the genetic variant of BS ously (14), and amplified products were separated on 0.5ϫ Tris- type 2 (MIM 600359) and lead to the clinical phenotype of borate-ethylenediaminetetra-acetic acid, 6% polyacrylamide gels run HPS/aBS (13–15). ROMK ensures functioning of the Na- under denaturing conditions (22). The gels were analyzed using Ge- K-2Cl cotransporter by recycling potassium back to the nescan 672 software, version 1.2 (Applied Biosystems), the Pharma- renal tubular lumen. cia Fragment Manager (Amersham Pharmacia), or autoradiography. 4. Mutations in the gene for the basolateral chloride channel Haplotypes were constructed from the genotype data. The most likely CLC-Kb (CLCNKB) cause the genetic variant of BS type 3 haplotypes were inferred by minimizing the number of crossover (MIM 602023), which is defined by a distinct subset of events in each sibship. patients in whom nephrocalcinosis is absent. Diagnosis in these patients is usually made during infancy or childhood Deletion Detection by PCR (16). No prenatal history
Load more

Recommended publications
  • Screening and Identification of Key Biomarkers in Clear Cell Renal Cell Carcinoma Based on Bioinformatics Analysis
    bioRxiv preprint doi: https://doi.org/10.1101/2020.12.21.423889; this version posted December 23, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Screening and identification of key biomarkers in clear cell renal cell carcinoma based on bioinformatics analysis Basavaraj Vastrad1, Chanabasayya Vastrad*2 , Iranna Kotturshetti 1. Department of Biochemistry, Basaveshwar College of Pharmacy, Gadag, Karnataka 582103, India. 2. Biostatistics and Bioinformatics, Chanabasava Nilaya, Bharthinagar, Dharwad 580001, Karanataka, India. 3. Department of Ayurveda, Rajiv Gandhi Education Society`s Ayurvedic Medical College, Ron, Karnataka 562209, India. * Chanabasayya Vastrad [email protected] Ph: +919480073398 Chanabasava Nilaya, Bharthinagar, Dharwad 580001 , Karanataka, India bioRxiv preprint doi: https://doi.org/10.1101/2020.12.21.423889; this version posted December 23, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract Clear cell renal cell carcinoma (ccRCC) is one of the most common types of malignancy of the urinary system. The pathogenesis and effective diagnosis of ccRCC have become popular topics for research in the previous decade. In the current study, an integrated bioinformatics analysis was performed to identify core genes associated in ccRCC. An expression dataset (GSE105261) was downloaded from the Gene Expression Omnibus database, and included 26 ccRCC and 9 normal kideny samples. Assessment of the microarray dataset led to the recognition of differentially expressed genes (DEGs), which was subsequently used for pathway and gene ontology (GO) enrichment analysis.
    [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]
  • Inherited Renal Tubulopathies—Challenges and Controversies
    G C A T T A C G G C A T genes Review Inherited Renal Tubulopathies—Challenges and Controversies Daniela Iancu 1,* and Emma Ashton 2 1 UCL-Centre for Nephrology, Royal Free Campus, University College London, Rowland Hill Street, London NW3 2PF, UK 2 Rare & Inherited Disease Laboratory, London North Genomic Laboratory Hub, Great Ormond Street Hospital for Children National Health Service Foundation Trust, Levels 4-6 Barclay House 37, Queen Square, London WC1N 3BH, UK; [email protected] * Correspondence: [email protected]; Tel.: +44-2381204172; Fax: +44-020-74726476 Received: 11 February 2020; Accepted: 29 February 2020; Published: 5 March 2020 Abstract: Electrolyte homeostasis is maintained by the kidney through a complex transport function mostly performed by specialized proteins distributed along the renal tubules. Pathogenic variants in the genes encoding these proteins impair this function and have consequences on the whole organism. Establishing a genetic diagnosis in patients with renal tubular dysfunction is a challenging task given the genetic and phenotypic heterogeneity, functional characteristics of the genes involved and the number of yet unknown causes. Part of these difficulties can be overcome by gathering large patient cohorts and applying high-throughput sequencing techniques combined with experimental work to prove functional impact. This approach has led to the identification of a number of genes but also generated controversies about proper interpretation of variants. In this article, we will highlight these challenges and controversies. Keywords: inherited tubulopathies; next generation sequencing; genetic heterogeneity; variant classification. 1. Introduction Mutations in genes that encode transporter proteins in the renal tubule alter kidney capacity to maintain homeostasis and cause diseases recognized under the generic name of inherited tubulopathies.
    [Show full text]
  • Inhibition of ROMK Channels by Low Extracellular K and Oxidative Stress
    Am J Physiol Renal Physiol 305: F208–F215, 2013. First published May 15, 2013; doi:10.1152/ajprenal.00185.2013. Inhibition of ROMK channels by low extracellular Kϩ and oxidative stress Gustavo Frindt,1 Hui Li,2 Henry Sackin,2 and Lawrence G. Palmer1 1Department of Physiology and Biophysics, Weill-Cornell Medical College, New York, New York; and 2Department of Physiology and Biophysics, The Chicago Medical School, Rosalind Franklin University, North Chicago, Illinois Submitted 2 April 2013; accepted in final form 8 May 2013 Frindt G, Li H, Sackin H, Palmer LG. Inhibition of ROMK may be essential for preventing Kϩ secretion and minimizing channels by low extracellular Kϩ and oxidative stress. Am J Physiol K losses. Renal Physiol 305: F208–F215, 2013. First published May 15, 2013; Measurements of ROMK activity in heterologous expression doi:10.1152/ajprenal.00185.2013.—We tested the hypothesis that low systems indicate that the channels are sensitive to changes in luminal Kϩ inhibits the activity of ROMK channels in the rat cortical ϩ ϩ ϩ the extracellular K concentration ([K ]o); decreases in [K ]o collecting duct. Whole-cell voltage-clamp measurements of the com- downregulate the channels (7, 28, 29, 31). One aspect of this Downloaded from ponent of outward Kϩ current inhibited by the bee toxin Tertiapin-Q ϩ response is a shift in the dependence of channel activity on (ISK) showed that reducing the bath concentration ([K ]o)to1mM intracellular pH, with low [Kϩ] moving the titration curve for resulted in a decline of current over 2 min compared with that o ϩ inhibition of the channels toward a higher, more physiological observed at 10 mM [K ]o.
    [Show full text]
  • Cldn19 Clic2 Clmp Cln3
    NewbornDx™ Advanced Sequencing Evaluation When time to diagnosis matters, the NewbornDx™ Advanced Sequencing Evaluation from Athena Diagnostics delivers rapid, 5- to 7-day results on a targeted 1,722-genes. A2ML1 ALAD ATM CAV1 CLDN19 CTNS DOCK7 ETFB FOXC2 GLUL HOXC13 JAK3 AAAS ALAS2 ATP1A2 CBL CLIC2 CTRC DOCK8 ETFDH FOXE1 GLYCTK HOXD13 JUP AARS2 ALDH18A1 ATP1A3 CBS CLMP CTSA DOK7 ETHE1 FOXE3 GM2A HPD KANK1 AASS ALDH1A2 ATP2B3 CC2D2A CLN3 CTSD DOLK EVC FOXF1 GMPPA HPGD K ANSL1 ABAT ALDH3A2 ATP5A1 CCDC103 CLN5 CTSK DPAGT1 EVC2 FOXG1 GMPPB HPRT1 KAT6B ABCA12 ALDH4A1 ATP5E CCDC114 CLN6 CUBN DPM1 EXOC4 FOXH1 GNA11 HPSE2 KCNA2 ABCA3 ALDH5A1 ATP6AP2 CCDC151 CLN8 CUL4B DPM2 EXOSC3 FOXI1 GNAI3 HRAS KCNB1 ABCA4 ALDH7A1 ATP6V0A2 CCDC22 CLP1 CUL7 DPM3 EXPH5 FOXL2 GNAO1 HSD17B10 KCND2 ABCB11 ALDOA ATP6V1B1 CCDC39 CLPB CXCR4 DPP6 EYA1 FOXP1 GNAS HSD17B4 KCNE1 ABCB4 ALDOB ATP7A CCDC40 CLPP CYB5R3 DPYD EZH2 FOXP2 GNE HSD3B2 KCNE2 ABCB6 ALG1 ATP8A2 CCDC65 CNNM2 CYC1 DPYS F10 FOXP3 GNMT HSD3B7 KCNH2 ABCB7 ALG11 ATP8B1 CCDC78 CNTN1 CYP11B1 DRC1 F11 FOXRED1 GNPAT HSPD1 KCNH5 ABCC2 ALG12 ATPAF2 CCDC8 CNTNAP1 CYP11B2 DSC2 F13A1 FRAS1 GNPTAB HSPG2 KCNJ10 ABCC8 ALG13 ATR CCDC88C CNTNAP2 CYP17A1 DSG1 F13B FREM1 GNPTG HUWE1 KCNJ11 ABCC9 ALG14 ATRX CCND2 COA5 CYP1B1 DSP F2 FREM2 GNS HYDIN KCNJ13 ABCD3 ALG2 AUH CCNO COG1 CYP24A1 DST F5 FRMD7 GORAB HYLS1 KCNJ2 ABCD4 ALG3 B3GALNT2 CCS COG4 CYP26C1 DSTYK F7 FTCD GP1BA IBA57 KCNJ5 ABHD5 ALG6 B3GAT3 CCT5 COG5 CYP27A1 DTNA F8 FTO GP1BB ICK KCNJ8 ACAD8 ALG8 B3GLCT CD151 COG6 CYP27B1 DUOX2 F9 FUCA1 GP6 ICOS KCNK3 ACAD9 ALG9
    [Show full text]
  • Ion Channels 3 1
    r r r Cell Signalling Biology Michael J. Berridge Module 3 Ion Channels 3 1 Module 3 Ion Channels Synopsis Ion channels have two main signalling functions: either they can generate second messengers or they can function as effectors by responding to such messengers. Their role in signal generation is mainly centred on the Ca2 + signalling pathway, which has a large number of Ca2+ entry channels and internal Ca2+ release channels, both of which contribute to the generation of Ca2 + signals. Ion channels are also important effectors in that they mediate the action of different intracellular signalling pathways. There are a large number of K+ channels and many of these function in different + aspects of cell signalling. The voltage-dependent K (KV) channels regulate membrane potential and + excitability. The inward rectifier K (Kir) channel family has a number of important groups of channels + + such as the G protein-gated inward rectifier K (GIRK) channels and the ATP-sensitive K (KATP) + + channels. The two-pore domain K (K2P) channels are responsible for the large background K current. Some of the actions of Ca2 + are carried out by Ca2+-sensitive K+ channels and Ca2+-sensitive Cl − channels. The latter are members of a large group of chloride channels and transporters with multiple functions. There is a large family of ATP-binding cassette (ABC) transporters some of which have a signalling role in that they extrude signalling components from the cell. One of the ABC transporters is the cystic − − fibrosis transmembrane conductance regulator (CFTR) that conducts anions (Cl and HCO3 )and contributes to the osmotic gradient for the parallel flow of water in various transporting epithelia.
    [Show full text]
  • Ion Channels
    UC Davis UC Davis Previously Published Works Title THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Ion channels. Permalink https://escholarship.org/uc/item/1442g5hg Journal British journal of pharmacology, 176 Suppl 1(S1) ISSN 0007-1188 Authors Alexander, Stephen PH Mathie, Alistair Peters, John A et al. Publication Date 2019-12-01 DOI 10.1111/bph.14749 License https://creativecommons.org/licenses/by/4.0/ 4.0 Peer reviewed eScholarship.org Powered by the California Digital Library University of California S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2019/20: Ion channels. British Journal of Pharmacology (2019) 176, S142–S228 THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Ion channels Stephen PH Alexander1 , Alistair Mathie2 ,JohnAPeters3 , Emma L Veale2 , Jörg Striessnig4 , Eamonn Kelly5, Jane F Armstrong6 , Elena Faccenda6 ,SimonDHarding6 ,AdamJPawson6 , Joanna L Sharman6 , Christopher Southan6 , Jamie A Davies6 and CGTP Collaborators 1School of Life Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK 2Medway School of Pharmacy, The Universities of Greenwich and Kent at Medway, Anson Building, Central Avenue, Chatham Maritime, Chatham, Kent, ME4 4TB, UK 3Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK 4Pharmacology and Toxicology, Institute of Pharmacy, University of Innsbruck, A-6020 Innsbruck, Austria 5School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, BS8 1TD, UK 6Centre for Discovery Brain Science, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties.
    [Show full text]
  • Therapeutic Approaches to Genetic Ion Channelopathies and Perspectives in Drug Discovery
    fphar-07-00121 May 7, 2016 Time: 11:45 # 1 REVIEW published: 10 May 2016 doi: 10.3389/fphar.2016.00121 Therapeutic Approaches to Genetic Ion Channelopathies and Perspectives in Drug Discovery Paola Imbrici1*, Antonella Liantonio1, Giulia M. Camerino1, Michela De Bellis1, Claudia Camerino2, Antonietta Mele1, Arcangela Giustino3, Sabata Pierno1, Annamaria De Luca1, Domenico Tricarico1, Jean-Francois Desaphy3 and Diana Conte1 1 Department of Pharmacy – Drug Sciences, University of Bari “Aldo Moro”, Bari, Italy, 2 Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari “Aldo Moro”, Bari, Italy, 3 Department of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro”, Bari, Italy 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. These diseases can range from common to very rare disorders and their severity can be mild, Edited by: disabling, or life-threatening. In spite of this, ion channels are the primary target of only Maria Cristina D’Adamo, University of Perugia, Italy about 5% of the marketed drugs suggesting their potential in drug discovery. The current Reviewed by: review summarizes the therapeutic management of the principal ion channelopathies Mirko Baruscotti, of central and peripheral nervous system, heart, kidney, bone, skeletal muscle and University of Milano, Italy Adrien Moreau, pancreas, resulting from mutations in calcium, sodium, potassium, and chloride ion Institut Neuromyogene – École channels.
    [Show full text]
  • Pflugers Final
    CORE Metadata, citation and similar papers at core.ac.uk Provided by Serveur académique lausannois A comprehensive analysis of gene expression profiles in distal parts of the mouse renal tubule. Sylvain Pradervand2, Annie Mercier Zuber1, Gabriel Centeno1, Olivier Bonny1,3,4 and Dmitri Firsov1,4 1 - Department of Pharmacology and Toxicology, University of Lausanne, 1005 Lausanne, Switzerland 2 - DNA Array Facility, University of Lausanne, 1015 Lausanne, Switzerland 3 - Service of Nephrology, Lausanne University Hospital, 1005 Lausanne, Switzerland 4 – these two authors have equally contributed to the study to whom correspondence should be addressed: Dmitri FIRSOV Department of Pharmacology and Toxicology, University of Lausanne, 27 rue du Bugnon, 1005 Lausanne, Switzerland Phone: ++ 41-216925406 Fax: ++ 41-216925355 e-mail: [email protected] and Olivier BONNY Department of Pharmacology and Toxicology, University of Lausanne, 27 rue du Bugnon, 1005 Lausanne, Switzerland Phone: ++ 41-216925417 Fax: ++ 41-216925355 e-mail: [email protected] 1 Abstract The distal parts of the renal tubule play a critical role in maintaining homeostasis of extracellular fluids. In this review, we present an in-depth analysis of microarray-based gene expression profiles available for microdissected mouse distal nephron segments, i.e., the distal convoluted tubule (DCT) and the connecting tubule (CNT), and for the cortical portion of the collecting duct (CCD) (Zuber et al., 2009). Classification of expressed transcripts in 14 major functional gene categories demonstrated that all principal proteins involved in maintaining of salt and water balance are represented by highly abundant transcripts. However, a significant number of transcripts belonging, for instance, to categories of G protein-coupled receptors (GPCR) or serine-threonine kinases exhibit high expression levels but remain unassigned to a specific renal function.
    [Show full text]
  • Ion Channels Accelerated D1scovery
    Quality Antibodies · Quality Results $-GeneTex Your Expertise Our Antibod1es Ion Channels Accelerated D1scovery --------- www.genetex.com Potassium (K+ ) Sodium (Na+ ) Calcium (Ca2+ ) Ion channels are pore-forming, usually multimeric plasma membrane proteins that can open and close in response to chemical, temperature, or mechanical signals. An open channel allows specific ions to rapid ly traverse the transmembrane passageway a long an electrochemical gradient, generating an electrical signal that is propagated along excitable cells. Ion channels are of immense importance in clinical medicine as they are linked to a broad array of disorders and are targets of an ever-expanding, and commonly prescribed, armamentarium of pharmacologic agents. Nevertheless, there remains a great void in our understanding of ion channel biology, which limits our ability to develop more effective andmo re specific drugs. GeneTex offers an outstanding selection of antibodies to support ion channel research.Please see the highlighted antibodies in this flyer or review our complete list of related products on the GeneTex website. Highlighted products HCNl antibody (GTX131334} DPP6 antibody (GTX133338} IP3 Receptor I antibody (GTX133104} (...___ ___w _w _w_ ._G_e_n_e_T_e_x_._c_o_m_ _____,) ` a n a 匱 。 'ot I: . ·""·,, " . 鼴 丶•' · ,' , `> ,,, 丶 B -- ,:: ·-- o .i :' T. 、 冨 ,. \\.◄ .•}' r<• .. , -·•Jt.<_,,,, . ◄ · ◄ / .Jj -~~ 盆;i . '. ., CACNB4 (GTX100202) VGluTl antibody (GTX133148) P2X7一 antibody (GTX104288) Cavl.2 antibody (GTX54754) Cav2.1 antibody (GTX54753)
    [Show full text]
  • Chloride Channelopathies Rosa Planells-Cases, Thomas J
    Chloride channelopathies Rosa Planells-Cases, Thomas J. Jentsch To cite this version: Rosa Planells-Cases, Thomas J. Jentsch. Chloride channelopathies. Biochimica et Biophysica Acta - Molecular Basis of Disease, Elsevier, 2009, 1792 (3), pp.173. 10.1016/j.bbadis.2009.02.002. hal- 00501604 HAL Id: hal-00501604 https://hal.archives-ouvertes.fr/hal-00501604 Submitted on 12 Jul 2010 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. ÔØ ÅÒÙ×Ö ÔØ Chloride channelopathies Rosa Planells-Cases, Thomas J. Jentsch PII: S0925-4439(09)00036-2 DOI: doi:10.1016/j.bbadis.2009.02.002 Reference: BBADIS 62931 To appear in: BBA - Molecular Basis of Disease Received date: 23 December 2008 Revised date: 1 February 2009 Accepted date: 3 February 2009 Please cite this article as: Rosa Planells-Cases, Thomas J. Jentsch, Chloride chan- nelopathies, BBA - Molecular Basis of Disease (2009), doi:10.1016/j.bbadis.2009.02.002 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form.
    [Show full text]
  • Dissociation of K Channel Density and ROMK Mrna in Rat Cortical Collecting Tubule During K Adaptation
    Dissociation of K channel density and ROMK mRNA in rat cortical collecting tubule during K adaptation GUSTAVO FRINDT, HAO ZHOU, HENRY SACKIN, AND LAWRENCE G. PALMER Department of Physiology and Biophysics, Cornell University Medical College, New York, New York 10021 Frindt, Gustavo, Hao Zhou, Henry Sackin, and mRNA coding for the channel and hence an increase in Lawrence G. Palmer. Dissociation of K channel density and the number of K channel proteins in the membrane. ROMK mRNA in rat cortical collecting tubule during K The cloning of the ROMK family of K channels, which is adaptation. Am. J. Physiol. 274 (Renal Physiol. 43): F525– believed to correspond to the SK channels in the CCT, F531, 1998.—The density of conducting K channels in the as well as in the thick ascending limb of the loop of apical membrane of the rat cortical collecting tubule (CCT) is increased by a high-K diet. To see whether this involved Henle (1, 6, 16), has enabled this idea to be examined. increased abundance of mRNA coding for K channel protein, In this study, we have used the technique of in situ we measured the relative amounts of mRNA for ROMK, the hybridization to directly test the hypothesis of transcrip- clone of the gene thought to encode the secretory K channel in tional control of K channels through dietary K. the CCT. Tubules were isolated and fixed for in situ hybridiza- tion with a probe based on the ROMK sequence. Radiolabeled METHODS probe associated with the tubule was quantified using densi- tometric analysis of the autoradiographic images of the Biological preparation.
    [Show full text]