The Lowe Oculocerebrorenal Syndrome

Human Genome Research

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Abstract

The oculocerebrorenal syndrome of Lowe is a rare X-linked metabolic disorder characterized by congenital cataracts, renal tubular dysfunction, and mental retardation. It is caused by mutations in the gene OCRL1 encoding a phosphatidylinositol 4,5 biphosphate 5-phosphatase. Work in my laboratory resulted in the identification of the responsible gene, determination of its biochemical function, and the development of accurate enzymatic diagnosis for affected fetuses and individuals. The current direction in the lab is to undrstand how a defect in this enzyme results in the various manifestations of the syndrome. We are working both in cultured human cells and in animal models. We have demonstrated that the actin cytoskeleton is disorganized in cultured fibroblasts from Lowe syndrome patients and that an excess of short F-actin filaments accumulate in a punctate distribution that colocalizes with both actin binding proteins gelsolin and alpha-actinin. We are currently investigating the role of intracellular calcium in bringing about this phenotype and have found abnormal calcium signalling in response to Gcopled protein receptor agonists in Lowe syndrome fibroblasts versus normal matched control fibroblast cells. we are also attemtping to create a mouse model for Lowe syndrome. Mice deficient in the murine ortholog of OCRL1 are normal. We suspect this is due to compensation by the murine ortholog of a human paralogous gene, INPP5B. We are creating a mouse deficient in both murine Ocrl1 and murine Inpp5b but carrying the human INPP5B gene, in order to mimic the situation in humans more closely. Transgenic animals carrying a BAC with INPP5B were created but did not express the human Inpp5b gene. As an alternative, we created transgenic animals epxressing the human Inpp5b cDNA epxressed off a beta-actin promoter. These mice were extremely ill at birth and died within a few days due to overexpression of the humna Inpp5b. We are now attempting to mimic the human gene by knocking in human exon 7 of Inpp5b into the endogenous mouse gene, since the only major difference between human and mouse inpp5b is in the way this exon is spliced. We have also collaborated with a group in Sycracuse New York to demonstrate that certain patients with mutations in the OCRL1 gene do not have Lowe syndrome but have a milder disorder, Dent disease, that is limited to the kidney and has some but not all of the proximal tubular defects seen in Lowe syndrome.