Back to Search
Start Over
Gain-of-function variants in CLCN7 cause hypopigmentation and lysosomal storage disease.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2024 Jul; Vol. 300 (7), pp. 107437. Date of Electronic Publication: 2024 Jun 03. - Publication Year :
- 2024
-
Abstract
- Together with its β-subunit OSTM1, ClC-7 performs 2Cl <superscript>-</superscript> /H <superscript>+</superscript> exchange across lysosomal membranes. Pathogenic variants in either gene cause lysosome-related pathologies, including osteopetrosis and lysosomal storage. CLCN7 variants can cause recessive or dominant disease. Different variants entail different sets of symptoms. Loss of ClC-7 causes osteopetrosis and mostly neuronal lysosomal storage. A recently reported de novo CLCN7 mutation (p.Tyr715Cys) causes widespread severe lysosome pathology (hypopigmentation, organomegaly, and delayed myelination and development, "HOD syndrome"), but no osteopetrosis. We now describe two additional HOD individuals with the previously described p.Tyr715Cys and a novel p.Lys285Thr mutation, respectively. Both mutations decreased ClC-7 inhibition by PI(3,5)P <subscript>2</subscript> and affected residues lining its binding pocket, and shifted voltage-dependent gating to less positive potentials, an effect partially conferred to WT subunits in WT/mutant heteromers. This shift predicts augmented pH gradient-driven Cl <superscript>-</superscript> uptake into vesicles. Overexpressing either mutant induced large lysosome-related vacuoles. This effect depended on Cl <superscript>-</superscript> /H <superscript>+</superscript> -exchange, as shown using mutants carrying uncoupling mutations. Fibroblasts from the p.Y715C patient also displayed giant vacuoles. This was not observed with p.K285T fibroblasts probably due to residual PI(3,5)P <subscript>2</subscript> sensitivity. The gain of function caused by the shifted voltage-dependence of either mutant likely is the main pathogenic factor. Loss of PI(3,5)P <subscript>2</subscript> inhibition will further increase current amplitudes, but may not be a general feature of HOD. Overactivity of ClC-7 induces pathologically enlarged vacuoles in many tissues, which is distinct from lysosomal storage observed with the loss of ClC-7 function. Osteopetrosis results from a loss of ClC-7, but osteoclasts remain resilient to increased ClC-7 activity.<br />Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.<br /> (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Humans
Gain of Function Mutation
Female
Male
Phosphatidylinositol Phosphates metabolism
HEK293 Cells
Vacuoles metabolism
Vacuoles genetics
Vacuoles pathology
Mutation, Missense
Membrane Proteins
Ubiquitin-Protein Ligases
Chloride Channels genetics
Chloride Channels metabolism
Lysosomal Storage Diseases genetics
Lysosomal Storage Diseases metabolism
Lysosomal Storage Diseases pathology
Lysosomes metabolism
Lysosomes genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 300
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 38838776
- Full Text :
- https://doi.org/10.1016/j.jbc.2024.107437