Abnormal ClC-3/TMEM9-mediated endosomal ion transport in CLCN3-associated neurodevelopmental disease
Year: 2026
Type: article
Study design: Observational Study
Abstract: Endolysosomal abnormalities are particularly detrimental to the nervous system and have been implicated in neuropsychiatric disorders. Key regulators of the lysosomal and endosomal luminal ion homeostasis are CLC chloride/proton exchangers. We report 15 individuals carrying variants in CLCN3 , encoding a ubiquitous endosomal 2Cl − /H + exchanger, and provide updated clinical information for 5 previously reported individuals. Subjects displayed a broad spectrum of neuropsychiatric symptoms, including developmental delay, intellectual disability, and epilepsy. To reveal the pathogenic mechanism, we investigated ClC-3 variants-mediated ion transport and its regulation by the recently discovered inhibitory beta subunit TMEM9. 12/20 missense variants exhibited altered properties and fell into two classes: those affecting the region binding inhibitory TMEM9 carboxy-termini, and those that broaden the voltage range over which ClC-3 conducts ions. Surprisingly, the latter variants also attenuated TMEM9-mediated inhibition. Both classes produced a toxic gain-of-function, as evident from endolysosomal vacuolization by mutant ClC-3/TMEM9 overexpression. Our results expand the genetic and clinical spectrum of CLCN3- related disease, provide a solid basis for genetic counseling, and uncover an unexpected link between gating-associated conformational changes and inhibition by TMEM9.
Source: EMBO Molecular Medicine
Authors: Maya M Polovitskaya, Tinatin Tkemaladze, Lotte Jensen, Sumanta Kar, Rosa Planells-Cases, Emanuele Agolini, Pankaj B Agrawal, Paolo Alfieri, Tahsin Stefan Barakat, Miriam Bertrand, Pamela Bowman, Alice S Brooks, Ange-Line Bruel, Sara Cabet, Karolina Chwialkowska, Giovanna Stefania Colafati, Julian Delanne, Laurence Faivre, Cristina Felton, Ute Grasshoff, Anne-Marie Guerrot, Tobias B Haack, Claudia Haase, Ashley R Helseth, Katrien Janssens, Amjad Khan, Margarete Koch-Hogrebe, Joshua Mandelberg, Elisabeth Mangold, Elene Melikidze, Marije Meuwissen, Ieva Mičule, Brittany Noble, Konrad Platzer, Dmitrijs Rots, Catherin Sarret, Ariane Schmetz, Amelle Shillington, Frédéric Tran-Mau-Them, Dagmar Wieczorek, Gaetan Lesca, Allan Bayat, Thomas J Jentsch
Institutions: University of Zurich, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Tbilisi State Medical University, Bambino Gesù Children's Hospital, University of Miami, Jackson Health System, Erasmus MC, University of Tübingen, Inserm, CHU Dijon Bourgogne, Centre de recherche Translationnelle en Médecine moléculaire, Université Bourgogne Europe, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Medical University of Białystok, University of Florida Health, University of Florida Health Science Center, Normandie Université, Université de Rouen Normandie, Helios Klinikum Erfurt, University of Antwerp, Antwerp University Hospital, The university of Lakki Marwat, Vestische Caritas-Kliniken, University of Bonn, University Hospital Bonn, Children's Clinical University Hospital, University Hospital Leipzig, Leipzig University, Riga Stradiņš University, Centre Hospitalier Universitaire de Clermont-Ferrand, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Düsseldorf University Hospital, Heinrich Heine University Düsseldorf, Lyon 1 Université, Centre National de la Recherche Scientifique, ERN EpiCARE, Laboratoire Physiopathologie et Génétique du Neurone et du Muscle, University of Southern Denmark, Filadelfia, NeuroCure Cluster of Excellence, Charité - Universitätsmedizin Berlin
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $7,990
Awards: G122924777, G1680808902, G2611185475, Nichtprogressive kongenitale Ataxie verbesserte Diagnose zur Eröffnung von Chancen für eine gezielte Therapie, EXC 2049: Comprehensive approaches to neurological and psychiatric disorders "NeuroCure", Reconstruction and Computational Modelling for Inherited Metabolic Diseases, G7578079922, G8203088156, G8291772589, G972790747
OpenAlex ID: W7170050398