The chloride antiporter CLCN7 is a modifier of lysosome dysfunction in FIG 4 and VAC14 mutants

Author summaryWe previously demonstrated that mutations in the genes FIG 4 and VAC14 are responsible for human neurological disorders. The pathogenic mechanism of these mutations affects lysosome function, and there are currently no effective treatments available. New therapies for genetic disorders may be developed by identifying modifier genes that interact with the primary causal gene. In the current work, we discovered that CLCN7 is a modifier of the lysosome dysfunction caused by FIG 4 and VAC14 mutations. Reducing CLCN7 expression corrected the structure of lysosomes in cultured cells and was also effective in a mouse model of FIG 4 deficiency. Down-regulation of CLCN7 thus provides a novel approach to treatment of these severe genetic disorders. The phosphatase FIG 4 and the scaffold protein VAC14 function in the biosynthesis of PI(3,5)P-2, a signaling lipid that inhibits the lysosomal chloride transporter ClC-7. Loss-of-function mutations of FIG 4 and VAC14 reduce PI(3,5)P-2 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 FIG 4 or VAC14. Knock-out of CLCN7 corrected lysosomal swelling and partially corrected lysosomal hyperacidification in FIG 4 null cell cultures. Knockout of the related transporter CLCN6 (ClC-6) in FIG 4 null cells did not affect the lysosome phenotype. In the Fig 4 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 FIG 4 and VAC14 disorders. Reduction of CLCN7 provides a new target for treatment of FIG 4 and VAC14 deficiencies that lack specific therapies, such as Charcot-Marie-Tooth Type 4J and Yunis-Varon syndrome.

Automated summary

CLCN7 functions as a modifier gene of lysosome dysfunction caused by FIG 4 and VAC14 mutations. Lowering CLCN7 expression can correct lysosomal structure and improve neurological function in FIG 4 deficient mice. This provides a novel approach for the treatment of these genetic disorders.