ABSTRACT Identification of genes responsible for genetic disease, analysis of their pathogenic mechanisms, and development of compensatory interventions constitute major goals of human genetics research. Identification of modifier genes and gene interaction can identify additional targets for intervention beyond the causal gene. Genetic or pharmacological targeting of modifiers may provide more effective avenues for treatment. We have focused on disorders with impaired function of ion channels and transporters that are localized in the membrane of the lysosome. Regulation of lysosomal ion transport is important to maintenance of acidic pH and osmolarity of the lysosome, as well as cytoplasmic ion concentration. During the current period, we evaluated modifiers of the phosphatase FIG4 that functions in biosynthesis of the signaling lipid PI(3,5)P2. Through genome-wide screens we identified the lysosomal co-transporter SLC12A9 as a modifier of FIG4 and the cause of a novel lysosomal disorder with neurological and skeletal defects. The PI(3,5)P2 regulated ion transporters are 'druggable targets' for development of therapy for PI(3,5)P2 deficiency disorders. We found that CLCN7 and PIP4K2C can compensate for FIG4 deficiency, based on their molecular functions. During the requested termination year, we will further define the pathogenic mechanisms of SLC12A9 transporter defects and interventions for the human disorder, and evaluate overexpression of PIKFYVE in Fig4 null mice using Crispr-a as potential genetic therapy for PI(3,5)P2 deficiency disorders. We will functionally characterize a recurrent FIG4 mutation in two patients with ALS. We will also distribute the mutant mouse lines that have been generated and publish the final papers from this long-running project. Together these aims extend our continuing studies of lysosome function and neurological disease.