Functional overlap between murine Inpp5b and Ocrl1 may explain why deficiency of the murine ortholog for OCRL1 does not cause Lowe syndrome in mice.

Abstract

The oculocerebrorenal syndrome of Lowe (OCRL) is an X-linked human genetic disorder characterized by mental retardation, congenital cataracts, and renal tubular dysfunction. The Lowe syndrome gene, OCRL1 , encodes a phosphatidylinositol 4,5-bisphosphate 5-phosphatase in the Golgi complex. The pathogenesis of Lowe syndrome due to deficiency of a phosphatidylinositol 4,5-bisphosphate 5-phosphatase in the Golgi complex is unknown. We have used targeted disruption in embryonic stem cells to make mice deficient in Ocrl1 , the mouse homologue for OCRL1 , as an animal model for the disease. Surprisingly, mice deficient in Ocrl1 do not develop the congenital cataracts, renal Fanconi syndrome, or neurological abnormalities seen in the human disorder. We hypothesized that Ocrl1 deficiency is complemented in mice by inositol polyphosphate 5-phosphatase ( Inpp5b ), an autosomal gene that encodes a phosphatidylinositol bisphosphate 5-phosphatase highly homologous to Ocrl1. We created mice deficient in Inpp5b ; the mice were viable and fertile without phenotype except for testicular degeneration in males beginning after sexual maturation. We crossed mice deficient in Ocrl1 to mice deficient in Inpp5b. No liveborn mice or embryos lacking both enzymes were found, demonstrating that Ocrl1 and Inpp5b have overlapping functions in mice and suggesting that the lack of phenotype in Ocrl1 -deficient mice may be due to compensating Inpp5b function. (

Identification of a Novel Domain in Two Mammalian Inositol-polyphosphate 5-Phosphatases That Mediates Membrane Ruffle Localization

“…Synaptojanin-1-deficient mice show accumulation of clathrin-coated vesicles in post-synaptic neurons and early death (15). Humans deficient in OCRL 5-phosphatase (16) demonstrate growth and mental retardation, renal tubular acidosis, and cataracts, although mice that lack this enzyme surprisingly show no phenotype (17). Homozygous male 5-phosphatase II-deficient mice are infertile due to disrupted sperm function (18).…”

Cloning and Characterization of a 72-kDa Inositol-polyphosphate 5-Phosphatase Localized to the Golgi Network

“…PtdIns (3,4,5)P 3 5-Phosphatase Assays-The preparation of 32 P-labeled PtdIns(3,4,5)P 3 substrate was undertaken as follows: 25 g of phosphatidylserine and 65 g of PtdIns(4,5)P 2 were mixed and dried under nitrogen and resuspended in 400 l of lipid resuspension buffer (20 mM Hepes, pH 7.5, 1 mM MgCl 2 , 1 mM EGTA) and sonicated for 5 min. 50 l of this suspension was added to 5 nmol of unlabeled ATP and 20 l of [␥-32 P]ATP (2 mCi, 3000 mCi/mmol), 5 l of 20ϫ kinase buffer (400 mM Hepes, pH 7.5, 100 mM MgCl 2 , 20 mM EGTA) and 1 g of affinity-purified recombinant PI 3-kinase in a reaction volume of 100 l (16).…”

“…Disruption in 5-phosphatase II results in testicular abnormalities. Mice deficient in both the OCRL protein and 5-phosphatase II die in utero (5). Collectively these studies suggest the 5-phosphatases have distinct functions that are nonredundant.…”

“…Targeted disruption of the type III 5-phosphatase SHIP, which has a restricted expression to hematopoietic cells, results in dramatic hyperplasia of myeloid cells in the bone marrow, spleen, and lungs, resembling a myeloproliferative syndrome (4). Although mice deficient in the OCRL protein demonstrate no phenotype (5), humans with mutations in this gene, Lowe's syndrome, demonstrate a variety of clinical features including growth and mental retardation, cataracts with severe visual impairment, renal Fanconi syndrome, and metabolic bone disease (6). Disruption in 5-phosphatase II results in testicular abnormalities.…”

The Inositol Polyphosphate 5-Phosphatases and the Apurinic/Apyrimidinic Base Excision Repair Endonucleases Share a Common Mechanism for Catalysis

“…However, mice with gene targeted deletion of OCRL show no phenotype, while 5-phosphatase II-deficient mice show little phenotype with the only noted abnormality being testicular abnormalities. Mice deficient in both OCRL and 5-phosphatase II die in utero (12). Underexpression of the 43-kDa 5-phosphatase using an antisense strategy results in enhanced intracellular calcium oscillations and cellular transformation (13,14).…”