The focus of our work is the oculocerebrorenal syndrome of Lowe (OCRL), a rare X-linked disorder characterized by bilateral congenital cataracts, mental retardation and renal Fanconi syndrome. Currently, no specific treatment for OCRL is available. We previously demonstrated that OCRL1 encodes a phosphatidylinositol 4,5 bisphosphate (PIP2) 5-phosphatase and developed a widely-used diagnostic and prenatal diagnostic test for the disorder. Ocrl1, expressed in most cells, is localized to the trans-Golgi and endosomes and may play a role in cell-cell contact formation, particularly in polarized cells where OCRL1 deficiency may affect the formation or stability of tight junctions. Although the Ocrl1 knockout mouse has no phenotype, a mouse knockout of the closest homolog to Ocrl1, Inpp5b, exhibits male infertility and abnormal germ cell adhesion. ? PIP2, the lipid substrate for ocrl1, is elevated in Lowe cells. PIP2 plays key roles in calcium signaling, actin reorganization, and vesicle budding. We have found that OCRL1 deficiency leads to actin cytoskeletal abnormalities, including an altered distribution of the actin binding protein, alpha-actinin. Because of the relationship between calcium and actin remodeling, we are studying whether abnormalities in calcium signaling occur in Lowe cells. We have recently found that Lowe patient fibroblasts show increased calcium signaling in response to bradykinin stimulation that was correlated with increased cell surface receptor, suggesting a role for OCRL1 in receptor trafficking. We have also found that patients with Dent disease, a form of renal Fanconi syndrome usually associated with mutations in a chloride channel gene (CLCN5), can instead have mutations in OCRL1. Our goals are: to understand how the chronic elevation of PIP2 affects cells and tissues, to understand the etiology of the OCRL phenotype, to investigate phenotypic heterogeneity in Lowe syndrome and to lay the groundwork for a disease-targeted treatment for OCRL.
| Lichter-Konecki, U; Farber, L W; Cronin, J S et al. (2006) The effect of missense mutations in the RhoGAP-homology domain on ocrl1 function. Mol Genet Metab 89:121-8 |
| Hoopes Jr, Richard R; Shrimpton, Antony E; Knohl, Stephen J et al. (2005) Dent Disease with mutations in OCRL1. Am J Hum Genet 76:260-7 |
