| Structural highlights
Disease
[OCRL_HUMAN] Defects in OCRL are the cause of Lowe oculocerebrorenal syndrome (OCRL) [MIM:309000]. It is an X-linked multisystem disorder affecting eyes, nervous system, and kidney. It is characterized by hydrophthalmia, cataract, mental retardation, vitamin D-resistant rickets, aminoaciduria, and reduced ammonia production by the kidney. Ocular abnormalities include cataract, glaucoma, microphthalmos, and decreased visual acuity. Developmental delay, hypotonia, behavior abnormalities, and areflexia are also present. Renal tubular involvement is characterized by impaired reabsorption of bicarbonate, amino acids, and phosphate. Musculoskeletal abnormalities such as joint hypermobility, dislocated hips, and fractures may develop as consequences of renal tubular acidosis and hypophosphatemia. Cataract is the only significant manifestation in carriers and is detected by slit-lamp examination.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] Defects in OCRL are the cause of Dent disease type 2 (DD2) [MIM:300555]. DD2 is a renal disease belonging to the 'Dent disease complex', a group of disorders characterized by proximal renal tubular defect, hypercalciuria, nephrocalcinosis, and renal insufficiency. The spectrum of phenotypic features is remarkably similar in the various disorders, except for differences in the severity of bone deformities and renal impairment. Characteristic abnormalities include low-molecular-weight proteinuria and other features of Fanconi syndrome, such as glycosuria, aminoaciduria, and phosphaturia, but typically do not include proximal renal tubular acidosis. Progressive renal failure is common, as are nephrocalcinosis and kidney stones.[11] [12] [13]
Function
[OCRL_HUMAN] Converts phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 4-phosphate. Also converts inositol 1,4,5-trisphosphate to inositol 1,4-bisphosphate and inositol 1,3,4,5-tetrakisphosphate to inositol 1,3,4-trisphosphate. May function in lysosomal membrane trafficking by regulating the specific pool of phosphatidylinositol 4,5-bisphosphate that is associated with lysosomes. Involved in primary cilia assembly.[14] [15]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Mutations in the inositol 5-phosphatase OCRL are responsible for Lowe syndrome, whose manifestations include mental retardation and renal Fanconi syndrome. OCRL has been implicated in membrane trafficking, but disease mechanisms remain unclear. We show that OCRL visits late-stage, endocytic clathrin-coated pits and binds the Rab5 effector APPL1 on peripheral early endosomes. The interaction with APPL1, which is mediated by the ASH-RhoGAP-like domains of OCRL and is abolished by disease mutations, provides a link to protein networks implicated in the reabsorptive function of the kidney and in the trafficking and signaling of growth factor receptors in the brain. Crystallographic studies reveal a role of the ASH-RhoGAP-like domains in positioning the phosphatase domain at the membrane interface and a clathrin box protruding from the RhoGAP-like domain. Our results support a role of OCRL in the early endocytic pathway, consistent with the predominant localization of its preferred substrates, PI(4,5)P(2) and PI(3,4,5)P(3), at the cell surface.
A role of the Lowe syndrome protein OCRL in early steps of the endocytic pathway.,Erdmann KS, Mao Y, McCrea HJ, Zoncu R, Lee S, Paradise S, Modregger J, Biemesderfer D, Toomre D, De Camilli P Dev Cell. 2007 Sep;13(3):377-90. PMID:17765681[16]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Swan LE, Tomasini L, Pirruccello M, Lunardi J, De Camilli P. Two closely related endocytic proteins that share a common OCRL-binding motif with APPL1. Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3511-6. doi:, 10.1073/pnas.0914658107. Epub 2010 Feb 2. PMID:20133602 doi:10.1073/pnas.0914658107
- ↑ Noakes CJ, Lee G, Lowe M. The PH domain proteins IPIP27A and B link OCRL1 to receptor recycling in the endocytic pathway. Mol Biol Cell. 2011 Mar 1;22(5):606-23. doi: 10.1091/mbc.E10-08-0730. Epub 2011, Jan 13. PMID:21233288 doi:10.1091/mbc.E10-08-0730
- ↑ Lin T, Orrison BM, Leahey AM, Suchy SF, Bernard DJ, Lewis RA, Nussbaum RL. Spectrum of mutations in the OCRL1 gene in the Lowe oculocerebrorenal syndrome. Am J Hum Genet. 1997 Jun;60(6):1384-8. PMID:9199559 doi:10.1086/515471
- ↑ Lin T, Orrison BM, Suchy SF, Lewis RA, Nussbaum RL. Mutations are not uniformly distributed throughout the OCRL1 gene in Lowe syndrome patients. Mol Genet Metab. 1998 May;64(1):58-61. PMID:9682219 doi:S1096-7192(98)92687-7
- ↑ Kawano T, Indo Y, Nakazato H, Shimadzu M, Matsuda I. Oculocerebrorenal syndrome of Lowe: three mutations in the OCRL1 gene derived from three patients with different phenotypes. Am J Med Genet. 1998 Jun 5;77(5):348-55. PMID:9632163
- ↑ Kubota T, Sakurai A, Arakawa K, Shimazu M, Wakui K, Furihata K, Fukushima Y. Identification of two novel mutations in the OCRL1 gene in Japanese families with Lowe syndrome. Clin Genet. 1998 Sep;54(3):199-202. PMID:9788721
- ↑ Monnier N, Satre V, Lerouge E, Berthoin F, Lunardi J. OCRL1 mutation analysis in French Lowe syndrome patients: implications for molecular diagnosis strategy and genetic counseling. Hum Mutat. 2000;16(2):157-65. PMID:10923037 doi:<157::AID-HUMU8>3.0.CO;2-9 10.1002/1098-1004(200008)16:2<157::AID-HUMU8>3.0.CO;2-9
- ↑ Roschinger W, Muntau AC, Rudolph G, Roscher AA, Kammerer S. Carrier assessment in families with lowe oculocerebrorenal syndrome: novel mutations in the OCRL1 gene and correlation of direct DNA diagnosis with ocular examination. Mol Genet Metab. 2000 Mar;69(3):213-22. PMID:10767176 doi:10.1006/mgme.1999.2955
- ↑ Yuksel A, Karaca E, Albayram MS. Magnetic resonance imaging, magnetic resonance spectroscopy, and facial dysmorphism in a case of Lowe syndrome with novel OCRL1 gene mutation. J Child Neurol. 2009 Jan;24(1):93-6. doi: 10.1177/0883073808321047. PMID:19168822 doi:10.1177/0883073808321047
- ↑ Hichri H, Rendu J, Monnier N, Coutton C, Dorseuil O, Poussou RV, Baujat G, Blanchard A, Nobili F, Ranchin B, Remesy M, Salomon R, Satre V, Lunardi J. From Lowe syndrome to Dent disease: correlations between mutations of the OCRL1 gene and clinical and biochemical phenotypes. Hum Mutat. 2011 Apr;32(4):379-88. doi: 10.1002/humu.21391. Epub 2011 Mar 10. PMID:21031565 doi:10.1002/humu.21391
- ↑ Hichri H, Rendu J, Monnier N, Coutton C, Dorseuil O, Poussou RV, Baujat G, Blanchard A, Nobili F, Ranchin B, Remesy M, Salomon R, Satre V, Lunardi J. From Lowe syndrome to Dent disease: correlations between mutations of the OCRL1 gene and clinical and biochemical phenotypes. Hum Mutat. 2011 Apr;32(4):379-88. doi: 10.1002/humu.21391. Epub 2011 Mar 10. PMID:21031565 doi:10.1002/humu.21391
- ↑ Hoopes RR Jr, Shrimpton AE, Knohl SJ, Hueber P, Hoppe B, Matyus J, Simckes A, Tasic V, Toenshoff B, Suchy SF, Nussbaum RL, Scheinman SJ. Dent Disease with mutations in OCRL1. Am J Hum Genet. 2005 Feb;76(2):260-7. Epub 2004 Dec 30. PMID:15627218 doi:10.1086/427887
- ↑ Sekine T, Nozu K, Iyengar R, Fu XJ, Matsuo M, Tanaka R, Iijima K, Matsui E, Harita Y, Inatomi J, Igarashi T. OCRL1 mutations in patients with Dent disease phenotype in Japan. Pediatr Nephrol. 2007 Jul;22(7):975-80. Epub 2007 Mar 24. PMID:17384968 doi:10.1007/s00467-007-0454-x
- ↑ Luo N, West CC, Murga-Zamalloa CA, Sun L, Anderson RM, Wells CD, Weinreb RN, Travers JB, Khanna H, Sun Y. OCRL localizes to the primary cilium: a new role for cilia in Lowe syndrome. Hum Mol Genet. 2012 Aug 1;21(15):3333-44. doi: 10.1093/hmg/dds163. Epub 2012 Apr , 27. PMID:22543976 doi:10.1093/hmg/dds163
- ↑ Coon BG, Hernandez V, Madhivanan K, Mukherjee D, Hanna CB, Barinaga-Rementeria Ramirez I, Lowe M, Beales PL, Aguilar RC. The Lowe syndrome protein OCRL1 is involved in primary cilia assembly. Hum Mol Genet. 2012 Apr 15;21(8):1835-47. doi: 10.1093/hmg/ddr615. Epub 2012 Jan , 6. PMID:22228094 doi:10.1093/hmg/ddr615
- ↑ Erdmann KS, Mao Y, McCrea HJ, Zoncu R, Lee S, Paradise S, Modregger J, Biemesderfer D, Toomre D, De Camilli P. A role of the Lowe syndrome protein OCRL in early steps of the endocytic pathway. Dev Cell. 2007 Sep;13(3):377-90. PMID:17765681 doi:http://dx.doi.org/10.1016/j.devcel.2007.08.004
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