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 ofFIG4andVAC14reduce PI(3,5)P2and result in lysosomal disorders characterized by accumulation of enlarged lysosomes and neurodegeneration. Similarly, a gain of function mutation ofCLCN7encoding ClC-7 also results in enlarged lysosomes. We therefore tested the ability of reducedCLCN7expression to compensate for loss ofFIG4orVAC14. Knock-out ofCLCN7corrected lysosomal swelling and partially corrected lysosomal hyperacidification inFIG4null cell cultures. Knockout of the related transporterCLCN6(ClC-6) inFIG4null cells did not affect the lysosome phenotype. In theFig4null mouse, reduction of ClC-7 by expression of the dominant negativeCLCN7variant p.Gly215Arg improved growth and neurological function and increased lifespan by 20%. These observations demonstrate a role for theCLCN7chloride transporter in pathogenesis ofFIG4andVAC14disorders. Reduction ofCLCN7provides a new target for treatment ofFIG4andVAC14deficiencies that lack specific therapies, such as Charcot-Marie-Tooth Type 4J and Yunis-Varón syndrome.