The chloride antiporter CLCN7 is a modifier of lysosome dysfunction in FIG4 and VAC14 mutants.

Autor: Cao X; Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, United States of America., Lenk GM; Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, United States of America., Mikusevic V; Membrane Transport Biophysics Section, National Institutes of Neurological Disorders and Stroke, Bethesda, Maryland, United States of America., Mindell JA; Membrane Transport Biophysics Section, National Institutes of Neurological Disorders and Stroke, Bethesda, Maryland, United States of America., Meisler MH; Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, United States of America.
Jazyk: angličtina
Zdroj: PLoS genetics [PLoS Genet] 2023 Jun 26; Vol. 19 (6), pp. e1010800. Date of Electronic Publication: 2023 Jun 26 (Print Publication: 2023).
DOI: 10.1371/journal.pgen.1010800
Abstrakt: 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.
Competing Interests: The authors have declared that no competing interests exist.
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Databáze: MEDLINE
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