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

Maya M Polovitskaya1,2, Tinatin Tkemaladze3,4, Lotte Jensen5

  • 1Leibniz Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany.

EMBO Molecular Medicine
|July 22, 2026
PubMed

Insights

Genetic variants in CLCN3, encoding a chloride/proton exchanger, cause neuropsychiatric disorders. These mutations lead to altered ion transport and endolysosomal abnormalities, revealing a toxic gain-of-function mechanism.

Area of Science:

  • Neuroscience
  • Genetics
  • Cell Biology

Background:

  • Endolysosomal abnormalities are linked to neurological and psychiatric conditions.
  • Chloride channel ClC-3 (encoded by CLCN3) is crucial for maintaining ion homeostasis in endosomes and lysosomes.
  • Dysfunction of CLC exchangers can disrupt neuronal function.

Purpose of the Study:

  • To investigate the genetic and clinical spectrum of CLCN3-related disorders.
  • To elucidate the pathogenic mechanisms of CLCN3 variants.
  • To understand the regulation of ClC-3 by the TMEM9 beta subunit.

Main Methods:

  • Clinical evaluation of 20 individuals with CLCN3 variants.
  • Functional characterization of ClC-3 variants in ion transport.
  • Investigation of TMEM9-mediated inhibition of ClC-3.
  • Assessment of endolysosomal morphology in cells expressing mutant ClC-3/TMEM9.

Main Results:

  • 15 new individuals with CLCN3 variants were identified, exhibiting diverse neuropsychiatric symptoms like developmental delay, intellectual disability, and epilepsy.
  • 12 of 20 missense variants showed altered ion transport properties.
  • Variants were classified based on their impact on TMEM9 binding or ion conduction properties.
  • Mutant ClC-3/TMEM9 overexpression induced endolysosomal vacuolization, indicating a toxic gain-of-function.

Conclusions:

  • CLCN3 variants represent a significant genetic cause of neuropsychiatric disorders.
  • Altered ClC-3 ion transport and impaired TMEM9 regulation contribute to disease pathogenesis.
  • The study reveals a novel connection between channel gating and TMEM9 inhibition, impacting endolysosomal function.

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