ArticlePLoS genetics2023
The chloride antiporter CLCN7 is a modifier of lysosome dysfunction in FIG4 and VAC14 mutants.
Article in PLoS genetics, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 15 citations in OpenAlex.
- Compartmental pH regulation in cancer and antitumor immunity: therapeutic opportunities and challenges.Apoptosis : an international journal on programmed cell death · 2026Review
- Spectrum and functions of ion channels and transporters in osteoclasts.Bone research · 2026Review
- TMEM175 does not function as a proton-selective ion channel to prevent lysosomal over-acidification.The Journal of cell biology · 2026Article
- LRRK2 integrates Rab and GABARAP interactions to sense and respond to distinct lysosomal stresses.bioRxiv : the preprint server for biology · 2025Article
- Mechanism of phosphoinositide regulation of lysosomal pH via inhibition of CLC-7.bioRxiv : the preprint server for biology · 2025Article
- Prevalence of loss-of-function, gain-of-function and dominant-negative mechanisms across genetic disease phenotypes.Nature communications · 2025Article
- Genetics of Skin, Hair, and Eye Color in Human Pigmentation Disorders.Annals of human genetics · 2025Review
- A novel frameshift variant leads to familial osteopetrosis with variable phenotypes in a Chinese Han consanguineous family.BMC medical genomics · 2025Article
- Genomic-Inbreeding Landscape and Selection Signatures in the Polo Argentino Horse Breed.International journal of molecular sciences · 2024Article
- Delayed vacuolation in mammalian cells caused by hypotonicity and ion loss.Scientific reports · 2024Article
- Distinct ClC-6 and ClC-7 ClThe Journal of physiology · 2023Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
The phosphatase FIG4 and the scaffold protein VAC14 function in the biosynthesis of PI(3,5)P2, a signaling lipid that inhibits the lysosomal chloride transporter ClC-7. Loss-of-function mutations of FIG4 and VAC14 reduce PI(3,5)P2 and result in lysosomal disorders characterized by accumulation of enlarged lysosomes and neurodegeneration. Similarly, a gain of function mutation of CLCN7 encoding ClC-7 also results in enlarged lysosomes. We therefore tested the ability of reduced CLCN7 expression to compensate for loss of FIG4 or VAC14. Knock-out of CLCN7 corrected lysosomal swelling and partially corrected lysosomal hyperacidification in FIG4 null cell cultures. Knockout of the related transporter CLCN6 (ClC-6) in FIG4 null cells did not affect the lysosome phenotype. In the Fig4 null mouse, reduction of ClC-7 by expression of the dominant negative CLCN7 variant p.Gly215Arg improved growth and neurological function and increased lifespan by 20%. These observations demonstrate a role for the CLCN7 chloride transporter in pathogenesis of FIG4 and VAC14 disorders. Reduction of CLCN7 provides a new target for treatment of FIG4 and VAC14 deficiencies that lack specific therapies, such as Charcot-Marie-Tooth Type 4J and Yunis-Varón syndrome.
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