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    OCRL Gene

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    Submitted by: Lily Guo
    (This entry belongs to Entry Collection "MedlinePlus ")

    Definition

    OCRL, inositol polyphosphate-5-phosphatase

    1. Introduction

    The OCRL gene provides instructions for making an enzyme that is present in cells throughout the body. This enzyme is part of a larger group of enzymes that modify fat (lipid) molecules known as membrane phospholipids. These molecules form the basic structure of cell membranes. Specifically, the OCRL enzyme regulates the levels of a membrane phospholipid called phosphatidylinositol 4,5-bisphosphate.

    The OCRL enzyme is found in several areas within cells. It is concentrated in a complex network of membranes known as the trans-Golgi network, which sorts proteins and other molecules and sends them to their intended destinations inside or outside the cell. The OCRL enzyme is also found on endosomes, specialized compartments that are formed at the cell surface to carry proteins and other molecules to their destinations within the cell.

    By controlling the level of phosphatidylinositol 4,5-bisphosphate, the OCRL enzyme helps regulate the transport of certain substances to and from the cell membrane and chemical signaling between cells. The enzyme may also be involved in the regulation of the actin cytoskeleton, which is a network of fibers that make up the cell's structural framework. The actin cytoskeleton has several critical functions, including determining cell shape and allowing cells to move.

    Recent research suggests that the OCRL enzyme is found in cell structures called primary cilia, which are microscopic, finger-like projections that stick out from the surface of cells and are involved in signaling pathways that transmit information between cells. Cilia are important for the structure and function of many types of cells, including cells in the brain, kidneys, and liver. Cilia are also necessary for the perception of sensory input (such as sight, hearing, and smell). Studies suggest that the OCRL enzyme may play a role in the formation, function, and maintenance of cilia.

    2. Health Conditions Related to Genetic Changes

    2.1. Dent disease

    At least 20 mutations in the OCRL gene have been found to cause Dent disease 2. This form of Dent disease is characterized by chronic kidney problems; some affected individuals also have mild intellectual disability, weak muscle tone (hypotonia), and clouding of the lens of the eyes (cataract) that does not impair vision. Some researchers consider Dent disease 2 to be a mild variant of Lowe syndrome, which is discussed below.

    The OCRL gene mutations that cause Dent disease 2 reduce or eliminate the function of the OCRL enzyme. These changes impair the transport of certain molecules and regulation of the actin cytoskeleton. They may also affect cell signaling by altering the structure or function of cilia. Disruption of these important cell activities likely impairs kidney function, leading to excess protein in the urine (proteinuria), kidney stones, and ultimately kidney failure. It is unknown how loss of the OCRL enzyme contributes to the other signs and symptoms of this condition.

    Because the OCRL enzyme is present throughout the body, it is unclear why Dent disease 2 primarily affects the kidneys and, to a lesser extent, the brain, eyes, and other tissues. It is possible that other enzymes may be able to compensate for the defective OCRL enzyme in unaffected tissues.

    2.3. Lowe syndrome

    More than 120 mutations in the OCRL gene have been identified in individuals with Lowe syndrome, a condition that affects the eyes, brain, and kidneys. Some of these mutations prevent the production of any OCRL enzyme. Other mutations reduce or eliminate the activity of the enzyme or prevent it from interacting with other proteins within the cell. Researchers believe that the effects of these genetic changes are similar to those of the mutations that cause Dent disease 2: the mutations likely alter the transport of molecules within cells, regulation of the actin cytoskeleton, and the structure and function of cilia. It is unknown why some OCRL gene mutations cause Lowe syndrome and others cause Dent disease 2.

    Because the OCRL enzyme is present throughout the body, it is unclear why Lowe syndrome primarily affects the kidney, brain, and eyes. As with Dent disease 2, it is possible that other enzymes may be able to compensate for the defective OCRL enzyme in unaffected tissues.

    3. Other Names for This Gene

    • INPP5F
    • LOCR
    • Lowe oculocerebrorenal syndrome protein
    • NPHL2
    • OCRL1
    • OCRL_HUMAN
    • oculocerebrorenal syndrome of Lowe
    • phosphatidylinositol polyphosphate 5-phosphatase

    This entry is adapted from https://medlineplus.gov/genetics/gene/ocrl

    References

    1. Attree O, Olivos IM, Okabe I, Bailey LC, Nelson DL, Lewis RA, McInnes RR,Nussbaum RL. The Lowe's oculocerebrorenal syndrome gene encodes a protein highly homologous to inositol polyphosphate-5-phosphatase. Nature. 1992 Jul16;358(6383):239-42.
    2. Choudhury R, Diao A, Zhang F, Eisenberg E, Saint-Pol A, Williams C,Konstantakopoulos A, Lucocq J, Johannes L, Rabouille C, Greene LE, Lowe M. Lowesyndrome protein OCRL1 interacts with clathrin and regulates protein trafficking between endosomes and the trans-Golgi network. Mol Biol Cell. 2005Aug;16(8):3467-79.
    3. Coon BG, Hernandez V, Madhivanan K, Mukherjee D, Hanna CB, Barinaga-RementeriaRamirez I, Lowe M, Beales PL, Aguilar RC. The Lowe syndrome protein OCRL1 isinvolved in primary cilia assembly. Hum Mol Genet. 2012 Apr 15;21(8):1835-47.doi: 10.1093/hmg/ddr615.
    4. 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.
    5. 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. FromLowe syndrome to Dent disease: correlations between mutations of the OCRL1 geneand clinical and biochemical phenotypes. Hum Mutat. 2011 Apr;32(4):379-88. doi:10.1002/humu.21391.
    6. 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 withmutations in OCRL1. Am J Hum Genet. 2005 Feb;76(2):260-7.Erratum in: Am J Hum Genet. 2007 Sep;81(3):634.
    7. Hyvola N, Diao A, McKenzie E, Skippen A, Cockcroft S, Lowe M. Membranetargeting and activation of the Lowe syndrome protein OCRL1 by rab GTPases. EMBO J. 2006 Aug 23;25(16):3750-61.
    8. Lowe M. Structure and function of the Lowe syndrome protein OCRL1. Traffic.2005 Sep;6(9):711-9. Review.
    9. 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 forcilia in Lowe syndrome. Hum Mol Genet. 2012 Aug 1;21(15):3333-44. doi:10.1093/hmg/dds163.
    10. McCrea HJ, Paradise S, Tomasini L, Addis M, Melis MA, De Matteis MA, DeCamilli P. All known patient mutations in the ASH-RhoGAP domains of OCRL affecttargeting and APPL1 binding. Biochem Biophys Res Commun. 2008 May 2;369(2):493-9.doi: 10.1016/j.bbrc.2008.02.067.
    11. Pirruccello M, De Camilli P. Inositol 5-phosphatases: insights from the Lowesyndrome protein OCRL. Trends Biochem Sci. 2012 Apr;37(4):134-43. doi:10.1016/j.tibs.2012.01.002.
    12. Utsch B, Bökenkamp A, Benz MR, Besbas N, Dötsch J, Franke I, Fründ S, Gok F,Hoppe B, Karle S, Kuwertz-Bröking E, Laube G, Neb M, Nuutinen M, Ozaltin F,Rascher W, Ring T, Tasic V, van Wijk JA, Ludwig M. Novel OCRL1 mutations inpatients with the phenotype of Dent disease. Am J Kidney Dis. 2006Dec;48(6):942.e1-14.
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