Fiche publication
Date publication
juillet 2026
Journal
EMBO molecular medicine
Auteurs
Membres identifiés du Cancéropôle Est :
Pr FAIVRE Laurence
Tous les auteurs :
Polovitskaya MM, Tkemaladze T, Jensen L, Kar S, Planells-Cases R, Agolini E, Agrawal PB, Alfieri P, Barakat TS, Bertrand M, Bowman P, Brooks AS, Bruel AL, Cabet S, Chwialkowska K, Colafati GS, Delanne J, Faivre L, Felton C, Grasshoff U, Guerrot AM, Haack TB, Haase C, Helseth AR, Janssens K, Khan A, Koch-Hogrebe M, Mandelberg J, Mangold E, Melikidze E, Meuwissen M, Mičule I, Noble B, Platzer K, Rots D, Sarret C, Schmetz A, Shillington A, Tran-Mau-Them F, Wieczorek D, Lesca G, Bayat A, Jentsch TJ
Lien Pubmed
Résumé
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.
Référence
EMBO Mol Med. 2026 07 22;:
