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<p>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 <i>CLCN3</i>, encoding a ubiquitous endosomal 2Cl<sup>−</sup>/H<sup>+</sup> 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 <i>CLCN3-</i>related disease, provide a solid basis for genetic counseling, and uncover an unexpected link between gating-associated conformational changes and inhibition by TMEM9.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月22日

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  • 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

摘要

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.