Lowe Syndrome (LS) is a devastating condition due to mutations in the OCRL1 gene that unfortunately leads to the early death of affected children. Although LS was described ~70 years ago, no specific treatment is available to patients. However, this project aims to change that situation. Further, since some OCRL1 mutations also cause the related Dent-2 (D2) disease, this project aims to benefit D2 patients as well. LS patients are born with cataracts, while mental retardation becomes evident with age and symptoms of kidney malfunction are detectable a month after birth. Lamentably, affected children die as a consequence of renal failure after adolescence. Since D2 patients also suffer of similar renal abnormalities including formation of kidney stones, this proposal is focused on kidney cells and phenotypes predicted to impact renal function. A perceived weakness of previous research is that even when most patients express mutated forms of the lipid phosphatase Ocrl1, most investigations in the field have been performed on model systems lacking OCRL1. In contrast, this proposal is completely centered in studying the phenotypic impact of Ocrl1 mutated variants found in patients. In that respect we found that although most OCRL1 patient missense mutations alter the phosphatase domain of Ocrl1, only about 50% of these changes affect residues within its active site. In other words, many patient mutations lead to Ocrl1 protein variants with intact binding/catalytic sequences. Further, our published results indicate that these variants are locked in conformations unable to process substrate. Therefore, we HYPOTHESIZE that a subset of Ocrl1 patient mutated proteins can re-acquire functionality by action of drugs able to stabilize the enzymatically active conformer (allosteric activators). These agents will have the unique ability to activate the patient own Ocrl1. Indeed, as a result of a series of small molecule screens performed in our lab, we identified several compounds, including FDA-approved drugs, able to restore the catalytic activity of 3 different Ocrl1 patient variants and to suppress a readout cellular phenotype. Nevertheless, their hypothesized allosteric mechanism of action, generalized applicability to multiple patient Ocrl1 variants and suppression of multiple phenotypes needs to be assessed.