Abnormal ClC-3/TMEM9-mediated endosomal ion transport in CLCN3-associated neurodevelopmental disease

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.

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Publication Details

Journal
EMBO Molecular Medicine
Published
2026-07-22
DOI
https://doi.org/10.1038/s44321-026-00486-6
Primary Topic
Calcium signaling and nucleotide metabolism
Type
article
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article

Abnormal ClC-3/TMEM9-mediated endosomal ion transport in CLCN3-associated neurodevelopmental disease

Giovanna Stefania Colafati, Emanuele Agolini, Konrad Platzer, Lotte Jensen et al.
EMBO Molecular Medicine
Calcium signaling and nucleotide metabolism
article

Abnormal ClC-3/TMEM9-mediated endosomal ion transport in CLCN3-associated neurodevelopmental disease

Giovanna Stefania Colafati, Emanuele Agolini, Konrad Platzer, Lotte Jensen, Thomas J. Jentsch, Karolina Chwiałkowska, Dmitrijs Rots, Ariane Schmetz, Katrien Janssens, Maya M. Polovitskaya, Pamela Bowman, Tahsin Stefan Barakat, Sara Cabet, Amjad Khan, Gaëtan Lesca, Paolo Alfieri, Ashley Helseth, Ange‐Line Bruel, Miriam Bertrand, Allan Bayat, Ieva Mičule, Elisabeth Mangold, Dagmar Wieczorek, Tinatin Tkemaladze, Rosa Planells‐Cases, Margarete Koch‐Hogrebe, Ute Grasshoff, Pankaj B. Agrawal, Alice S. Brooks, Elene Melikidze, Amelle Shillington, Frederic Tran-Mau-Them, Marije Meuwissen, Claudia Haase, Anne-Marie Guerrot, Julian Delanne, Tobias B Haack, Joshua Mandelberg, Sumanta Kar, Brittany Noble, Laurence Faivre, Catherin Sarret, Cristina Felton
article en

Abstract

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.

EMBO Molecular Medicine
Université Claude Bernard Lyon 1 (FR), Cincinnati Children's Hospital Medical Center (US), Centre National de la Recherche Scientifique (FR), University of Bonn (DE), University of Miami (US), Medical University of Białystok (PL), Inserm (FR), Université de Bourgogne (FR), University of Southern Denmark (DK), University Hospital Bonn (DE), Royal Devon & Exeter NHS Foundation Trust (GB), Erasmus MC (NL), Jacksonville University (US), Hôpital Femme Mère Enfant (FR), Düsseldorf University Hospital (DE), Jackson Health System (US), Klinikum Vest (DE), Leibniz-Forschungsinstitut für Molekulare Pharmakologie (DE), Hospices Civils de Lyon (FR), Antwerp University Hospital (BE), Normandie Université (FR), Children's Clinical University Hospital (LV), Medizinisches Versorgungszentrum Prof. Mathey, Prof. Schofer (DE), Bambino Gesù Children's Hospital (IT), Department of Mathematical Sciences (RU), Institut NeuroMyoGène (FR), Riga Stradiņš University (LV), Levine Children's Hospital (US), Centre Hospitalier Universitaire de Clermont-Ferrand (FR), Society for Developmental and Behavioral Pediatrics (US), Helios Klinikum Erfurt (DE), Heinrich Heine University Düsseldorf (DE), Université de Rouen Normandie (FR), Tbilisi State Medical University (GE), Charité - Universitätsmedizin Berlin (DE), University of Tübingen (DE), University of Cincinnati Medical Center (US), Leipzig University (DE), HCL Technologies (India) (IN)
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Calcium signaling and nucleotide metabolism
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