title: 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.
authors.affiliation: Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19102, USA.
authors.forename: P A
authors.initials: PA
authors.lastname: Jänne
authors.forename: S F
authors.initials: SF
authors.lastname: Suchy
authors.forename: D
authors.initials: D
authors.lastname: Bernard
authors.forename: M
authors.initials: M
authors.lastname: MacDonald
authors.forename: J
authors.initials: J
authors.lastname: Crawley
authors.forename: A
authors.initials: A
authors.lastname: Grinberg
authors.forename: A
authors.initials: A
authors.lastname: Wynshaw-Boris
authors.forename: H
authors.initials: H
authors.lastname: Westphal
authors.forename: R L
authors.initials: RL
authors.lastname: Nussbaum
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000652:urine; D000818:Animals; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D015870:Gene Expression / Q000235:genetics; D018390:Gene Targeting; D006801:Humans; D000072181:Inositol Polyphosphate 5-Phosphatases; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009043:Motor Activity / Q000502:physiology; D009800:Oculocerebrorenal Syndrome / Q000235:genetics* / Q000503:physiopathology; D010641:Phenotype; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics* / Q000502:physiology; D011506:Proteins / Q000235:genetics* / Q000502:physiology; D012326:RNA Splicing; D012333:RNA, Messenger / Q000378:metabolism; D013234:Stem Cells; D000099182:Phosphoinositide 5-Phosphatases
chemical_list: D000596:Amino Acids; D000072181:Inositol Polyphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases; D011506:Proteins; D012333:RNA, Messenger; D000099182:Phosphoinositide 5-Phosphatases; C075695:OCRL protein, human; C489581:Ocrl protein, mouse