Genetic and molecular analyses of the Lowe syndrome gene (OCRL-1) and its highly related homologue inositol polyphosphate 5-phosphatase (INPP5B)

Pasi Antero Janne, University of Pennsylvania


Lowe syndrome or OCRL is an X-linked human genetic disorder characterized by mental retardation, congenital cataracts and renal Fanconi syndrome, a proximal tubular dysfunction. The gene for OCRL, OCRL-1, is localized to the Xq25-q26 region and was isolated through standard positional cloning techniques. Biochemically, the protein product of the OCRL-1 gene is a phosphatidyl inositol 4,5-bisphosphate 5-phosphatase. In an attempt to further understand the pathogenesis of Lowe syndrome and to create a potential animal model, we have used targeted disruption in embryonic stem cells in order to make mice deficient in Ocrl-1. These mice share the molecular and biochemical defects of human Lowe syndrome but do not develop congenital cataracts, renal Fanconi syndrome or mental retardation as seen in the human disorder. As a way to understand this discrepancy between humans and mice we have begun to identify and study OCRL-1 related genes since they could compensate for the lack of Ocrl-1 in our mice. Database searches reveal seven human genes that share four highly conserved domains. The most closely related gene to OCRL-1 is INPP5B which encodes for a 75 kDa inositol polyphosphate 5-phosphatase and is 53% identical at the amino acid level. Initial genetic studies of INPP5B have focused on identifyng its chromosomal location in both humans and mice. Our studies show that human INPP5B maps to chromosome 1p34. In mice, Inpp5b maps to distal chromosome 4, a homologous position to human 1p34. Inpp5b maps near a previously identified mouse mutation called dysgenetic lens (dyl), a congenital cataract mutation. However, using a genetic approach we could show that they are two separate loci, Inpp5b being more distal on chromosome 4 than dyl. In order to formally test if Inpp5b compensates for Ocrl-1 we have attempted to make mice deficient in Inpp5b. Much like the $Ocrl\sp-$ mice these mice develop normally without any obvious phenotypic consequences. However, a molecular analysis of these mice shows that the targeted Inpp5b mice are not completely null at the Inpp5b locus. The targeting event causes a splicing back into frame with a subsequent deletion of 10 amino acids which are highly conserved. The targeted Inpp5b mRNA is found at normal levels in brain but is decreased to about 10% of normal in other tissues examined. Future experiments will include additional breeding in order to generate the "double knock-out" mice to test if Inpp5b compensates for the lack of Ocrl-1. In addition, further studies are needed on the targeted Inpp5b mice to determine the effect of this mutation on protein stability and biochemical function. These studies provide genetic tools which can be further used to study PIP$\sb2$ metabolism in mice to understand differences that exist in this pathway between humans and mice.

Subject Area

Genetics|Pathology|Cellular biology

Recommended Citation

Janne, Pasi Antero, "Genetic and molecular analyses of the Lowe syndrome gene (OCRL-1) and its highly related homologue inositol polyphosphate 5-phosphatase (INPP5B)" (1996). Dissertations available from ProQuest. AAI9627940.