Specific OCRL1 patient mutations differentially impact Lowe Syndrome cellular phenotypes

Lowe Syndrome (LS) is a lethal genetic disorder caused by mutations in the OCRL1 gene, which encodes the lipid 5 phosphatase Ocrl1. Patients exhibit a characteristic triad of symptoms including eyes, brain and kidneys abnormalities with renal failure as the most common cause of death. Over 200 OCRL1 mutations have been identified in LS, but their specific impact on cellular processes is unknown. Despite observations of heterogeneity in LS patient symptoms, there is little understanding of the correlation between the genotype of patients and disease and/or cellular phenotypes. Here, we showed that different mutations had diverse effects on protein localization, stability and on triggering LS cellular phenotypes. In addition, mutations in specific domains imparted unique characteristics to the resulting mutated protein. We also propose that some mutations conformationally affect the 5-phosphatase domain of the protein, resulting in additional phenotypes and loss of activity. This study is the first to show the differential effect of patient 5-phosphatase mutations on cellular phenotypes and introduces a conformational disease component in LS. This work can provide a framework that can help stratify patients as well as provide a more accurate prognosis depending on the nature and location of the mutation in the OCRL1 gene and its effect on the biochemical activity of Ocrl1.