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Your search keyword '"Chloride Channels/genetics"' showing total 4 results
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4 results on '"Chloride Channels/genetics"'

1. Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition

Author

Elizabeth E. Palmer, Michael Pusch, Alessandra Picollo, Caitlin Forwood, Matthew H. Nguyen, Vanessa Suckow, Jessica Gibbons, Alva Hoff, Lisa Sigfrid, Andre Megarbane, Mathilde Nizon, Benjamin Cogné, Claire Beneteau, Fowzan S. Alkuraya, Aziza Chedrawi, Mais O. Hashem, Hannah Stamberger, Sarah Weckhuysen, Arnaud Vanlander, Berten Ceulemans, Sulekha Rajagopalan, Kenneth Nunn, Stéphanie Arpin, Martine Raynaud, Constance S. Motter, Catherine Ward-Melver, Katrien Janssens, Marije Meuwissen, Diane Beysen, Nicola Dikow, Mona Grimmel, Tobias B. Haack, Emma Clement, Amy McTague, David Hunt, Sharron Townshend, Michelle Ward, Linda J. Richards, Cas Simons, Gregory Costain, Lucie Dupuis, Roberto Mendoza-Londono, Tracy Dudding-Byth, Jackie Boyle, Carol Saunders, Emily Fleming, Salima El Chehadeh, Marie-Aude Spitz, Amelie Piton, Bénédicte Gerard, Marie-Thérèse Abi Warde, Gillian Rea, Caoimhe McKenna, Sofia Douzgou, Siddharth Banka, Cigdem Akman, Jennifer M. Bain, Tristan T. Sands, Golder N. Wilson, Erin J. Silvertooth, Lauren Miller, Damien Lederer, Rani Sachdev, Rebecca Macintosh, Olivier Monestier, Deniz Karadurmus, Felicity Collins, Melissa Carter, Luis Rohena, Marjolein H. Willemsen, Charlotte W. Ockeloen, Rolph Pfundt, Sanne D. Kroft, Michael Field, Francisco E. R. Laranjeira, Ana M. Fortuna, Ana R. Soares, Vincent Michaud, Sophie Naudion, Sailaja Golla, David D. Weaver, Lynne M. Bird, Jennifer Friedman, Virginia Clowes, Shelagh Joss, Laura Pölsler, Philippe M. Campeau, Maria Blazo, Emilia K. Bijlsma, Jill A. Rosenfeld, Christian Beetz, Zöe Powis, Kirsty McWalter, Tracy Brandt, Erin Torti, Mikaël Mathot, Shekeeb S. Mohammad, Ruth Armstrong, Vera M. Kalscheuer, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - (MGD) Service de pédiatrie, Growth and Development, Pediatrics, Centre for Medical Genetics, Brussels Heritage Lab, and Medical Genetics

Subjects
Male, DISRUPTION, Chloride Channels/genetics, EXCHANGER, Mutation, Missense, LYSOSOMAL STORAGE DISEASE, VARIANTS, Neurodevelopmental Disorders/genetics, PHENOTYPE, Cellular and Molecular Neuroscience, All institutes and research themes of the Radboud University Medical Center, Genes, X-Linked, CLC CHLORIDE, Medicine and Health Sciences, Humans, Molecular Biology, MUTATION, Biology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], CHANNELS, LINKED MENTAL-RETARDATION, ASSOCIATION, GENE, Psychiatry and Mental health, Chemistry, Female, Human medicine
Abstract

Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a “shift” of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.

Published
2023
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2. Gitelman syndrome: consensus and guidance from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference

Author

Martin Konrad, David H. Ellison, Shih-Hua Lin, Rosa Vargas-Poussou, Anne Blanchard, Olivier Devuyst, Detlef Bockenhauer, Davide Bolignano, Lorenzo A. Calò, Nine V A M Knoers, Fiona E. Karet Frankl, Etienne Cosyns, University of Zurich, Devuyst, Olivier, Blanchard, Anne [0000-0002-0815-0586], Bolignano, Davide [0000-0003-3032-245X], Ellison, David H [0000-0003-2915-265X], Apollo - University of Cambridge Repository, CIC - HEGP (CIC 1418), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), University College of London [London] (UCL), Great Ormond Street Hospital for Children [London] (GOSH), Consiglio Nazionale delle Ricerche / National Research Council [Calabria, Italy] (CNR), Universita degli Studi di Padova, Wanze [Belgium], Universität Zürich [Zürich] = University of Zurich (UZH), Oregon Health and Science University [Portland] (OHSU), University of Cambridge [UK] (CAM), Cambridge University Hospitals - NHS (CUH), University Medical Center [Utrecht], University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), National Taiwan University [Taiwan] (NTU), Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte (MARHEA), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Università degli Studi di Padova = University of Padua (Unipd), Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte [CHU-Necker] (MARHEA), and HULOT, Jean-Sébastien

Subjects
Calcium/urine, Sodium Chloride, Dietary/therapeutic use, Consensus Development Conferences as Topic, 030232 urology & nephrology, Anti-Inflammatory Agents, Angiotensin-Converting Enzyme Inhibitors, Disease, 030204 cardiovascular system & hematology, Sodium Chloride, thiazide-sensitive sodium-chloride cotransporter, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, 10052 Institute of Physiology, 0302 clinical medicine, Gitelman Syndrome/complications, Diagnosis, salt-losing tubulopathy, Medicine, Potassium/administration & dosage, Magnesium, Solute Carrier Family 12, Member 3, Ultrasonography, 2727 Nephrology, Magnesium/administration & dosage, medicine.diagnostic_test, Anti-Inflammatory Agents, Non-Steroidal, Dietary/therapeutic use, Bartter Syndrome/blood, Angiotensin Receptor Antagonists/therapeutic use, 3. Good health, Angiotensin-Converting Enzyme Inhibitors/therapeutic use, Chondrocalcinosis/etiology, Phenotype, Nephrology, Practice Guidelines as Topic, Anti-Inflammatory Agents, Non-Steroidal/therapeutic use, medicine.symptom, Gitelman Syndrome, medicine.medical_specialty, Non-Steroidal/therapeutic use, Solute Carrier Family 12, Chloride Channels/genetics, 610 Medicine & health, Chondrocalcinosis, Hypokalemia, Hypocalciuria, Diagnosis, Differential, 03 medical and health sciences, hypomagnesemia, Angiotensin Receptor Antagonists, Rare Diseases/genetics, Rare Diseases, Tubulopathy, Chloride Channels, Journal Article, Humans, Genetic Testing, Salt intake, Sodium Chloride, Dietary, Intensive care medicine, Genetic testing, business.industry, Bartter Syndrome, Gitelman syndrome, medicine.disease, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, hypokalemic metabolic alkalosis, Differential, Member 3/genetics, Dietary Supplements, Mutation, Hypokalemia/blood, Potassium, Quality of Life, 570 Life sciences, biology, Calcium, SLC12A3, Differential diagnosis, Solute Carrier Family 12, Member 3/genetics, business, Kidney disease
Abstract

International audience; Gitelman syndrome (GS) is a rare, salt-losing tubulopathy characterized by hypokalemic metabolic alkalosis with hypomagnesemia and hypocalciuria. The disease is recessively inherited, caused by inactivating mutations in the SLC12A3 gene that encodes the thiazide-sensitive sodium-chloride cotransporter (NCC). GS is usually detected during adolescence or adulthood, either fortuitously or in association with mild or nonspecific symptoms or both. The disease is characterized by high phenotypic variability and a significant reduction in the quality of life, and it may be associated with severe manifestations. GS is usually managed by a liberal salt intake together with oral magnesium and potassium supplements. A general problem in rare diseases is the lack of high quality evidence to inform diagnosis, prognosis, and management. We report here on the current state of knowledge related to the diagnostic evaluation, follow-up, management, and treatment of GS; identify knowledge gaps; and propose a research agenda to substantiate a number of issues related to GS. This expert consensus statement aims to establish an initial framework to enable clinical auditing and thus improve quality control of care.

Published
2017
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3. The murine choroid plexus epithelium expresses the 2Cl-/H+-exchanger ClC-7 and Na+/H+ exchanger NHE6 in the luminal membrane domain

Author

Henriette L. Christensen, Jeppe Praetorius, Robert A. Fenton, Inga Baasch Christensen, Qi Wu, and Helle Hasager Damkier

Subjects
0301 basic medicine, Male, Spectrometry, Mass, Electrospray Ionization, Chloride Channels/genetics, Physiology, Intracellular pH, Choroid plexus, Membrane Potentials, Cell membrane, 03 medical and health sciences, Cerebrospinal fluid, Choroid Plexus Epithelium, medicine, Journal Article, Animals, Choroid Plexus/cytology, Mass spectrometry, Chemistry, Cell Membrane/metabolism, Cell Biology, Acid-base transport, Hydrogen-Ion Concentration, Flow Cytometry, Epithelium, Epithelial Cells/metabolism, Transport protein, Cell biology, Mice, Inbred C57BL, Sodium–hydrogen antiporter, 030104 developmental biology, medicine.anatomical_structure, Cerebrospinal Fluid/metabolism, Proteomics/methods, Cell Separation/methods, Sodium-Hydrogen Exchangers/genetics
Abstract

The choroid plexus epithelium within the brain ventricles secretes the majority of the cerebrospinal fluid (CSF). The luminal Na+-K+-ATPase acts in concert with a host of other transport proteins to mediate efficient fluid secretion across the epithelium. The CSF contains little protein buffer, but the pH value seems nonetheless maintained within narrow limits, even when faced with acid-base challenges. The involvement of choroid plexus acid-base transporters in CSF pH regulation is highlighted by the expression of several acid-base transporters in the epithelium. The aim of the present study was to identify novel acid-base transporters expressed in the luminal membrane of the choroid plexus epithelium to pave the way for systematic investigations of each candidate transporter in the regulation of CSF pH. Mass spectrometry analysis of proteins from epithelial cells isolated by fluorescence-activated cell sorting identified the Cl−/H+ exchangers ClC-3, -4, -5, and -7 in addition to known choroid plexus acid-base transporters. RT-PCR on FACS isolated epithelial cells confirmed the expression of the corresponding mRNAs, as well as Na+/H+ exchanger NHE6 mRNA. Both NHE6 and ClC-7 were immunolocalized to the luminal plasma membrane domain of the choroid plexus epithelial cells. Dynamic imaging of intracellular pH and membrane potential changes in isolated choroid plexus epithelial cells demonstrated Cl− gradient-driven changes in intracellular pH and membrane potential that are consistent with Cl−/H+ exchange. In conclusion, we have detected for the first time NHE6 and ClC-7 in the choroid plexus, which are potentially involved in pH regulation of the CSF.

Published
2018
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4. Clinical utility gene card for: Gitelman syndrome

Author

Olivier Devuyst, Erik-Jan Kamsteeg, Nine V A M Knoers, UCL - SSS/IREC/NEFR - Pôle de Néphrologie, and UCL - (SLuc) Service de néphrologie

Subjects
Receptors, Drug - genetics, medicine.medical_specialty, Chloride Channels/genetics, Solute Carrier Family 12, Member 3, Receptors, Drug, 030232 urology & nephrology, Biology, Genomic disorders and inherited multi-system disorders [IGMD 3], 03 medical and health sciences, Gitelman Syndrome/genetics, 0302 clinical medicine, Chloride Channels, Internal medicine, Receptors, Genetics, medicine, Hum, Humans, Solute Carrier Family 12, Member 3, Gene, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Symporters/genetics, Chloride Channels - genetics, Symporters, Gitelman syndrome, medicine.disease, Endocrinology, Gitelman Syndrome - genetics, Drug/genetics, Mutation (genetic algorithm), Mutation, Clinical Utility Gene Card, Genetics and epigenetic pathways of disease Renal disorder [NCMLS 6], Symporters - genetics, Gitelman Syndrome, Receptors, Drug/genetics
Abstract

Knoers, Nine Vam Devuyst, Olivier Kamsteeg, Erik-Jan Research Support, Non-U.S. Gov't England Eur J Hum Genet. 2011 Aug;19(8). doi: 10.1038/ejhg.2011.14. Epub 2011 Feb 23.

Published
2011

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