The Lowe's oculocerebrorenal syndrome gene encodes a protein highly homologous to inositol polyphosphate-5-phosphatase

Attree, Olivier; Im, Olivos; Okabe, Ichiro; Lc, Bailey; Dl, Nelson; Ra, Lewis; Rr, McInnes; Nussbaum, RL

doi:10.1038/358239a0

Cited by 452 publications

(327 citation statements)

References 26 publications

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“…Lowe Syndrome is mediated by mutations in the gene encoding a member of the inositol-5-phosphatase protein family, OCRL [1]. Recently, mutations in this gene have also been described in patients with Dent disease, a condition involving kidney reabsorption defects similar to those observed in Lowe syndrome [2].…”

Section: Introductionmentioning

confidence: 99%

All known patient mutations in the ASH-RhoGAP domains of OCRL affect targeting and APPL1 binding

McCrea

Paradise

Tomasini

et al. 2008

Biochemical and Biophysical Research Communications

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Mutations in the inositol 5-phosphatase OCRL are responsible for Lowe syndrome, an X-linked disorder characterized by bilateral cataracts, mental retardation, neonatal hypotonia, and renal Fanconi syndrome, and for Dent disease, another X-linked condition characterized by kidney reabsorption defects. We have previously described an interaction of OCRL with the endocytic adaptor APPL1 that links OCRL to protein networks involved in the disease phenotype. Here we provide new evidence showing that among the interactions which target OCRL to membranes of the endocytic pathway, binding to APPL1 is the only one abolished by all known disease-causing missense mutations in the ASH-RhoGAP domains of the protein. Furthermore, we demonstrate that APPL1 and rab5 independently contribute to recruit OCRL to enlarged endosomes induced by the expression of constitutively active Rab5. Thus, binding to APPL1 helps localize OCRL at specific cellular sites, and disruption of this interaction may play a role in disease.

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Section: Introductionmentioning

confidence: 99%

All known patient mutations in the ASH-RhoGAP domains of OCRL affect targeting and APPL1 binding

McCrea

Paradise

Tomasini

et al. 2008

Biochemical and Biophysical Research Communications

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“…The OCRL gene is located on chromosome Xq25-26 and its genomic structure has been partly elucidated (Attree et al, 1992;Nussbaum et al, 1997). The gene contains 24 exons, the coding region including exons 2-24.…”

Section: Introductionmentioning

confidence: 99%

OCRLMutation analysis in Italian patients with Lowe syndrome

et al. 2004

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The oculocerebrorenal syndrome of Lowe (OCRL, also called OCRL1) is a rare X-linked disorder characterized by major abnormalities of eyes, nervous system, and kidneys. The gene responsible for OCRL was identified by positional cloning and encodes an inositol polyphosphate-5-phosphatase. We performed the molecular analysis in 9 Italian patients and 26 relatives and we detected the mutations in all the examined patients. Eight mutations out of nine had never been described and consisted of truncating mutations (frameshift, nonsense, splice site and genomic deletion), and missense mutations. The mutations were distributed in the second half of the gene as previously described in other populations. In three cases the mutations were absent in the mothers confirming the occurrence of novel mutations in this disorder. Our results on the Italian population are similar to the data previously obtained in other populations.

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“…PTEN was subsequently shown to be a phosphatase, which dephosphorylates phosphatidylinositol 3,4,5-trisphosphate to generate phosphatidylinositol 4,5-bisphosphate, an activity that is lost in patients with PTEN mutations (4,5). Mutations in the inositol polyphosphate 5-phosphatase OCRL cause the X-linked disorder Lowe syndrome, which is associated with mental retardation, blindness, and renal failure (6). Mutations in myotubularin cause myotubular myopathy (7), and mutations in myotubularin-related protein 2 (MTMR2) and MTMR13 cause a form of Charcot Marie Tooth disease type 4B, a demyelinating neurodegenerative disorder (8,9).…”

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confidence: 99%

Myotubularin-related protein (MTMR) 9 determines the enzymatic activity, substrate specificity, and role in autophagy of MTMR8

Zou¹,

Zhang²,

Marjanovic

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The myotubularins are a large family of inositol polyphosphate 3-phosphatases that, despite having common substrates, subsume unique functions in cells that are disparate. The myotubularin family consists of 16 different proteins, 9 members of which possess catalytic activity, dephosphorylating phosphatidylinositol 3-phosphate [PtdIns(3)P] and phosphatidylinositol 3,5-bisphosphate [PtdIns(3,5)P 2 ] at the D-3 position. Seven members are inactive because they lack the conserved cysteine residue in the CX 5 R motif required for activity. We studied a subfamily of homologous myotubularins, including myotubularin-related protein 6 (MTMR6), MTMR7, and MTMR8, all of which dimerize with the catalytically inactive MTMR9. Complex formation between the active myotubularins and MTMR9 increases their catalytic activity and alters their substrate specificity, wherein the MTMR6/R9 complex prefers PtdIns(3,5)P 2 as substrate; the MTMR8/R9 complex prefers PtdIns(3)P. MTMR9 increased the enzymatic activity of MTMR6 toward PtdIns(3,5)P 2 by over 30-fold, and enhanced the activity toward PtdIns(3)P by only 2-fold. In contrast, MTMR9 increased the activity of MTMR8 by 1.4-fold and 4-fold toward PtdIns (3,5)P 2 and PtdIns(3)P, respectively. In cells, the MTMR6/R9 complex significantly increases the cellular levels of PtdIns(5)P, the product of PI(3,5)P 2 dephosphorylation, whereas the MTMR8/R9 complex reduces cellular PtdIns(3)P levels. Consequentially, the MTMR6/R9 complex serves to inhibit stress-induced apoptosis and the MTMR8/R9 complex inhibits autophagy.I nositol lipids play important roles in a variety of intracellular signaling pathways. In response to stimuli, the phosphoinositide profile is regulated by phospholipases, lipid kinases, and phosphatases. Understanding the roles of inositol signaling has expanded during the last decade and a number of these enzymes have been shown to cause diseases when mutated (1). The tumor-suppressor PTEN was discovered through positional cloning as being mutated in several types of cancer (2, 3). PTEN was subsequently shown to be a phosphatase, which dephosphorylates phosphatidylinositol 3,4,5-trisphosphate to generate phosphatidylinositol 4,5-bisphosphate, an activity that is lost in patients with PTEN mutations (4, 5). Mutations in the inositol polyphosphate 5-phosphatase OCRL cause the X-linked disorder Lowe syndrome, which is associated with mental retardation, blindness, and renal failure (6). Mutations in myotubularin cause myotubular myopathy (7), and mutations in myotubularin-related protein 2 (MTMR2) and MTMR13 cause a form of Charcot Marie Tooth disease type 4B, a demyelinating neurodegenerative disorder (8, 9).The myotubularin family consists of 16 different proteins, 9 members of which possess catalytic activity (10, 11) and 7 members that are inactive. Myotubularin proteins are not redundant and have unique functions within cells by regulating a specific pool of dephosphorylating phosphatidylinositol 3-phosphate [PtdIns(3)P] and phosphatidylinositol 3,5-bisphosphate [PtdIns (3...

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The Lowe's oculocerebrorenal syndrome gene encodes a protein highly homologous to inositol polyphosphate-5-phosphatase

Cited by 452 publications

References 26 publications

All known patient mutations in the ASH-RhoGAP domains of OCRL affect targeting and APPL1 binding

All known patient mutations in the ASH-RhoGAP domains of OCRL affect targeting and APPL1 binding

OCRLMutation analysis in Italian patients with Lowe syndrome

Myotubularin-related protein (MTMR) 9 determines the enzymatic activity, substrate specificity, and role in autophagy of MTMR8

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