Key Points
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OCRL mutations cause Lowe syndrome, an X-linked disease characterized by congenital cataracts, central nervous system involvement and renal Fanconi syndrome; the only available treatments are surgery for cataracts and symptomatic care for renal dysfunction
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OCRL encodes a 5-phosphatase that acts preferentially on phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), a phosphoinositide with a pivotal role in intracellular trafficking; disease-causing mutations occur throughout the OCRL gene, but mainly in exons 9–15, which encode the catalytic domain
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Mutations in OCRL also cause Dent disease 2, a milder condition that results in renal Fanconi syndrome similar to that of Dent disease 1, caused by mutations in the gene that encodes the endosomal chloride channel ClC-5
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OCRL localizes mainly in endolysosomal compartments; its dysfunction causes an accumulation of PI(4,5)P2 resulting in delayed recycling of receptors required for protein reabsorption and impairment of the lysosomal–autophagic pathway
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Mouse and zebrafish animal models of Lowe syndrome are available, but these do not fully recapitulate the manifestations of Lowe syndrome
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Areas for future research include the mechanisms underlying the tissue selective manifestations of Lowe syndrome and Dent disease 2 as well as the identification of effective therapeutic strategies
Abstract
Lowe syndrome is an X-linked disease that is characterized by congenital cataracts, central hypotonia, intellectual disability and renal Fanconi syndrome. The disease is caused by mutations in OCRL, which encodes an inositol polyphosphate 5-phosphatase (OCRL) that acts on phosphoinositides — quantitatively minor constituents of cell membranes that are nonetheless pivotal regulators of intracellular trafficking. In this Review we summarize the considerable progress made over the past decade in understanding the cellular roles of OCRL in regulating phosphoinositide balance along the endolysosomal pathway, a fundamental system for the reabsorption of proteins and solutes by proximal tubular cells. We discuss how studies of OCRL have led to important discoveries about the basic mechanisms of membrane trafficking and describe the key features and limitations of the currently available animal models of Lowe syndrome. Mutations in OCRL can also give rise to a milder pathology, Dent disease 2, which is characterized by renal Fanconi syndrome in the absence of extrarenal pathologies. Understanding how mutations in OCRL give rise to two clinical entities with differing extrarenal manifestations represents an opportunity to identify molecular pathways that could be targeted to develop treatments for these conditions.
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References
Eckardt, K. U. et al. Evolving importance of kidney disease: from subspecialty to global health burden. Lancet 382, 158–169 (2013).
Devuyst, O. et al. Rare inherited kidney diseases: challenges, opportunities, and perspectives. Lancet 383, 1844–1859 (2014).
Kriz, W. & Kaissling, B. in Seldin and Giebisch's The Kidney 5th edn (eds Alpern, R., Caplan, M. & Moe, O.) (Academic Press, 2013).
Christensen, E. I. & Birn, H. Megalin and cubilin: multifunctional endocytic receptors. Nat. Rev. Mol. Cell Biol. 3, 256–266 (2002).
Dickson, L. E., Wagner, M. C., Sandoval, R. M. & Molitoris, B. A. The proximal tubule and albuminuria: really! J. Am. Soc. Nephrol. 25, 443–453 (2014).
Nielsen, R. & Christensen, E. I. Proteinuria and events beyond the slit. Pediatr. Nephrol. 25, 813–822 (2010).
Coudroy, G. et al. Contribution of cubilin and amnionless to processing and membrane targeting of cubilin-amnionless complex. J. Am. Soc. Nephrol. 16, 2330–2337 (2005).
Fyfe, J. C. et al. The functional cobalamin (vitamin B12)-intrinsic factor receptor is a novel complex of cubilin and amnionless. Blood 103, 1573–1579 (2004).
Mishra, S. K. et al. Disabled-2 exhibits the properties of a cargo-selective endocytic clathrin adaptor. EMBO J. 21, 4915–4926 (2002).
Gekle, M. Renal tubule albumin transport. Annu. Rev. Physiol. 67, 573–594 (2005).
Faundez, V. & Hartzell, H. C. Intracellular chloride channels: determinants of function in the endosomal pathway. Sci. STKE 2004, re8 (2004).
Hurtado-Lorenzo, A. et al. V-ATPase interacts with ARNO and Arf6 in early endosomes and regulates the protein degradative pathway. Nat. Cell Biol. 8, 124–136 (2006).
Herak-Kramberger, C. M., Brown, D. & Sabolic, I. Cadmium inhibits vacuolar H+-ATPase and endocytosis in rat kidney cortex. Kidney Int. 53, 1713–1726 (1998).
Plans, V., Rickheit, G. & Jentsch, T. J. Physiological roles of CLC Cl−/H + exchangers in renal proximal tubules. Pflugers Arch. 458, 23–37 (2009).
Stauber, T. & Jentsch, T. J. Chloride in vesicular trafficking and function. Annu. Rev. Physiol. 75, 453–477 (2013).
Tenten, V. et al. Albumin is recycled from the primary urine by tubular transcytosis. J. Am. Soc. Nephrol. 24, 1966–1980 (2013).
Havasi, A. & Dong, Z. Autophagy and tubular cell death in the kidney. Semin. Nephrol. 36, 174–188 (2016).
Zhen, Y. & Stenmark, H. Cellular functions of Rab GTPases at a glance. J. Cell Sci. 128, 3171–3176 (2015).
Jean, S. & Kiger, A. A. Coordination between RAB GTPase and phosphoinositide regulation and functions. Nat. Rev. Mol. Cell Biol. 13, 463–470 (2012).
Merrifield, C. J. & Kaksonen, M. Endocytic accessory factors and regulation of clathrin-mediated endocytosis. Cold Spring Harb. Perspect. Biol. 6, a016733 (2014).
Praetorius, H. A. The primary cilium as sensor of fluid flow: new building blocks to the model. A review in the theme: cell signaling: proteins, pathways and mechanisms. Am. J. Physiol. Cell Physiol. 308, C198–C208 (2015).
Igarashi, T. in Pediatric Nephrology: Sixth Completely Revised, Updated and Enlarged Edition (eds Avner, E., Harmon, W., Niaudet, P. & Yoshikawa, N.) 1039–1067 (Springer Berlin Heidelberg, 2009).
Terryn, S. et al. Tubular proteinuria in patients with HNF1alpha mutations: HNF1alpha drives endocytosis in the proximal tubule. Kidney Int. 89, 1075–1089 (2016).
Devuyst, O. & Thakker, R. V. Dent's disease. Orphanet J. Rare Dis. 5, 28 (2010).
Baines, R. J. & Brunskill, N. J. Tubular toxicity of proteinuria. Nat. Rev. Nephrol. 7, 177–180 (2011).
Luciani, A. et al. Impaired lysosomal function underlies monoclonal light chain-associated renal Fanconi syndrome. J. Am. Soc. Nephrol. 27, 2049–2061 (2016).
Boger, C. A. et al. CUBN is a gene locus for albuminuria. J. Am. Soc. Nephrol. 22, 555–570 (2011).
Pattaro, C. et al. Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function. Nat. Commun. 7, 10023 (2016).
Lowe, C. U., Terrey, M. & Mac, L. E. Organic-aciduria, decreased renal ammonia production, hydrophthalmos, and mental retardation; a clinical entity. AMA Am. J. Dis. Child. 83, 164–184 (1952).
Richards, W., Donnell, G. N., Wilson, W. A., Stowens, D. & Perry, T. The oculo-cerebro-renal syndrome of Lowe. Am. J. Dis. Child. 109, 185–203 (1965).
Attree, O. et al. The Lowe's oculocerebrorenal syndrome gene encodes a protein highly homologous to inositol polyphosphate-5-phosphatase. Nature 358, 239–242 (1992).
Loi, M. Lowe syndrome. Orphanet J. Rare Dis. 1, 16 (2006).
Lewis, R. A., Nussbaum, R. L. & Brewer, E. D. Lowe syndrome. GeneReviews https://www.ncbi.nlm.nih.gov/books/NBK1480/ (updated 23 Feb 2012).
Staiano, L., De Leo, M. G., Persico, M. & De Matteis, M. A. Mendelian disorders of PI metabolizing enzymes. Biochim. Biophys. Acta 1851, 867–881 (2015).
Mueller, O. T. et al. Lowe oculocerebrorenal syndrome in a female with a balanced X;20 translocation: mapping of the X chromosome breakpoint. Am. J. Hum. Genet. 49, 804–810 (1991).
Cau, M. et al. A locus for familial skewed X chromosome inactivation maps to chromosome Xq25 in a family with a female manifesting Lowe syndrome. J. Hum. Genet. 51, 1030–1036 (2006).
Bockenhauer, D. et al. Renal phenotype in Lowe syndrome: a selective proximal tubular dysfunction. Clin. J. Am. Soc. Nephrol. 3, 1430–1436 (2008).
Kleta, R. Fanconi or not Fanconi? Lowe syndrome revisited. Clin. J. Am. Soc. Nephrol. 3, 1244–1245 (2008).
McSpadden, K. Living with Lowe syndrome: a guide for families, friends and professionals. 3rd edn. (Lowe Syndrome Association Inc, 2000).
Zaniew, M. et al. Long-term renal outcome in children with OCRL mutations: retrospective analysis of a large international cohort. Nephrol. Dial Transplant. http://dx.doi.org/10.1093/ndt/gfw350 (2016).
Pasternack, S. M. et al. A premature termination mutation in a patient with Lowe syndrome without congenital cataracts: dropping the “O” in OCRL. Klin. Padiatr. 225, 29–33 (2013).
Recker, F. et al. Characterization of 28 novel patients expands the mutational and phenotypic spectrum of Lowe syndrome. Pediatr. Nephrol. 30, 931–943 (2015).
Tripathi, R. C., Cibis, G. W. & Tripathi, B. J. Pathogenesis of cataracts in patients with Lowe's syndrome. Ophthalmology 93, 1046–1051 (1986).
Roschinger, W., Muntau, A. C., Rudolph, G., Roscher, A. A. & 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. 69, 213–222 (2000).
Park, E. et al. Muscle involvement in Dent disease 2. Pediatr. Nephrol. 29, 2127–2132 (2014).
Charnas, L. et al. MRI findings and peripheral neuropathy in Lowe's syndrome. Neuropediatrics 19, 7–9 (1988).
Allmendinger, A. M., Desai, N. S., Burke, A. T., Viswanadhan, N. & Prabhu, S. Neuroimaging and renal ultrasound manifestations of oculocerebrorenal syndrome of Lowe. J. Radiol. Case Rep. 8, 1–7 (2014).
Carroll, W. J., Woodruff, W. W. & Cadman, T. E. MR findings in oculocerebrorenal syndrome. AJNR Am. J. Neuroradiol. 14, 449–451 (1993).
Demmer, L. A., Wippold, F. J. II & Dowton, S. B. Periventricular white matter cystic lesions in Lowe (oculocerebrorenal) syndrome. A new MR finding. Pediatr. Radiol. 22, 76–77 (1992).
Ono, J., Harada, K., Mano, T., Yamamoto, T. & Okada, S. MR findings and neurologic manifestations in Lowe oculocerebrorenal syndrome. Pediatr. Neurol. 14, 162–164 (1996).
Sener, R. N. Lowe syndrome: proton MR spectroscopy, and diffusion MR imaging. J. Neuroradiol. 31, 238–240 (2004).
Bokenkamp, A. et al. Dent-2 disease: a mild variant of Lowe syndrome. J. Pediatr. 155, 94–99 (2009).
Charnas, L. R., Bernardini, I., Rader, D., Hoeg, J. M. & Gahl, W. A. Clinical and laboratory findings in the oculocerebrorenal syndrome of Lowe, with special reference to growth and renal function. N. Engl. J. Med. 324, 1318–1325 (1991).
Lasne, D. et al. Bleeding disorders in Lowe syndrome patients: evidence for a link between OCRL mutations and primary haemostasis disorders. Br. J. Haematol. 150, 685–688 (2010).
Lloyd, S. E. et al. A common molecular basis for three inherited kidney stone diseases. Nature 379, 445–449 (1996).
Hoopes, R. R. Jr et al. Dent disease with mutations in OCRL1. Am. J. Hum. Genet. 76, 260–267 (2005).
Bockenhauer, D. et al. Novel OCRL mutations in patients with Dent-2 disease. Pediatr. Genet. 1, 15–23 (2012).
Hsu, F. & Mao, Y. The structure of phosphoinositide phosphatases: insights into substrate specificity and catalysis. Biochim. Biophys. Acta 1851, 698–710 (2015).
Astle, M. V. et al. Regulation of phosphoinositide signaling by the inositol polyphosphate 5-phosphatases. IUBMB Life 58, 451–456 (2006).
Schmid, A. C., Wise, H. M., Mitchell, C. A., Nussbaum, R. & Woscholski, R. Type II phosphoinositide 5-phosphatases have unique sensitivities towards fatty acid composition and head group phosphorylation. FEBS Lett. 576, 9–13 (2004).
Mao, Y. et al. A PH domain within OCRL bridges clathrin-mediated membrane trafficking to phosphoinositide metabolism. EMBO J. 28, 1831–1842 (2009).
Ponting, C. P. A novel domain suggests a ciliary function for ASPM, a brain size determining gene. Bioinformatics 22, 1031–1035 (2006).
Peck, J., Douglas, G. IV, Wu, C. H. & Burbelo, P. D. Human RhoGAP domain-containing proteins: structure, function and evolutionary relationships. FEBS Lett. 528, 27–34 (2002).
Faucherre, A. et al. Lowe syndrome protein OCRL1 interacts with Rac GTPase in the trans-Golgi network. Hum. Mol. Genet. 12, 2449–2456 (2003).
Jefferson, A. B. & Majerus, P. W. Properties of type II inositol polyphosphate 5-phosphatase. J. Biol. Chem. 270, 9370–9377 (1995).
Hichri, H. et al. From Lowe syndrome to Dent disease: correlations between mutations of the OCRL1 gene and clinical and biochemical phenotypes. Hum. Mutat. 32, 379–388 (2011).
Montjean, R. et al. OCRL-mutated fibroblasts from patients with Dent-2 disease exhibit INPP5B-independent phenotypic variability relatively to Lowe syndrome cells. Hum. Mol. Genet. 24, 994–1006 (2015).
Shrimpton, A. E. et al. OCRL1 mutations in Dent 2 patients suggest a mechanism for phenotypic variability. Nephron Physiol. 112, 27–36 (2009).
Choudhury, R. et al. Lowe syndrome protein OCRL1 interacts with clathrin and regulates protein trafficking between endosomes and the trans-Golgi network. Mol. Biol. Cell 16, 3467–3479 (2005).
Ungewickell, A., Ward, M. E., Ungewickell, E. & Majerus, P. W. The inositol polyphosphate 5-phosphatase Ocrl associates with endosomes that are partially coated with clathrin. Proc. Natl Acad. Sci. USA 101, 13501–13506 (2004).
Hyvola, N. et al. Membrane targeting and activation of the Lowe syndrome protein OCRL1 by rab GTPases. EMBO J. 25, 3750–3761 (2006).
Rodriguez-Gabin, A. G. et al. Interaction of Rab31 and OCRL-1 in oligodendrocytes: its role in transport of mannose 6-phosphate receptors. J. Neurosci. Res. 88, 589–604 (2010).
Fukuda, M., Kanno, E., Ishibashi, K. & Itoh, T. Large scale screening for novel rab effectors reveals unexpected broad Rab binding specificity. Mol. Cell. Proteomics 7, 1031–1042 (2008).
Hagemann, N., Hou, X., Goody, R. S., Itzen, A. & Erdmann, K. S. Crystal structure of the Rab binding domain of OCRL1 in complex with Rab8 and functional implications of the OCRL1/Rab8 module for Lowe syndrome. Small GTPases 3, 107–110 (2012).
Dambournet, D. et al. Rab35 GTPase and OCRL phosphatase remodel lipids and F-actin for successful cytokinesis. Nat. Cell Biol. 13, 981–988 (2011).
Coon, B. G. et al. The Lowe syndrome protein OCRL1 is involved in primary cilia assembly. Hum. Mol. Genet. 21, 1835–1847 (2012).
Ben El Kadhi, K., Emery, G. & Carreno, S. The unexpected role of Drosophila OCRL during cytokinesis. Commun. Integr. Biol. 5, 291–293 (2012).
Wang, H. R. et al. Regulation of cell polarity and protrusion formation by targeting RhoA for degradation. Science 302, 1775–1779 (2003).
Gu, Y. et al. Hematopoietic cell regulation by Rac1 and Rac2 guanosine triphosphatases. Science 302, 445–449 (2003).
Faucherre, A. et al. Lowe syndrome protein Ocrl1 is translocated to membrane ruffles upon Rac GTPase activation: a new perspective on Lowe syndrome pathophysiology. Hum. Mol. Genet. 14, 1441–1448 (2005).
Nandez, R. et al. A role of OCRL in clathrin-coated pit dynamics and uncoating revealed by studies of Lowe syndrome cells. eLife 3, e02975 (2014).
Allen, P. G. Actin filament uncapping localizes to ruffling lamellae and rocketing vesicles. Nat. Cell Biol. 5, 972–979 (2003).
Coon, B. G. et al. Lowe syndrome patient fibroblasts display Ocrl1-specific cell migration defects that cannot be rescued by the homologous Inpp5b phosphatase. Hum. Mol. Genet. 18, 4478–4491 (2009).
Bohdanowicz, M., Balkin, D. M., De Camilli, P. & Grinstein, S. Recruitment of OCRL and Inpp5B to phagosomes by Rab5 and APPL1 depletes phosphoinositides and attenuates Akt signaling. Mol. Biol. Cell 23, 176–187 (2012).
Shin, H. W. et al. An enzymatic cascade of Rab5 effectors regulates phosphoinositide turnover in the endocytic pathway. J. Cell Biol. 170, 607–618 (2005).
Vicinanza, M. et al. OCRL controls trafficking through early endosomes via PtdIns4,5P2-dependent regulation of endosomal actin. EMBO J. 30, 4970–4985 (2011).
De Leo, M. G. et al. Autophagosome-lysosome fusion triggers a lysosomal response mediated by TLR9 and controlled by OCRL. Nat. Cell Biol. 18, 839–850 (2016).
Saftig, P. & Klumperman, J. Lysosome biogenesis and lysosomal membrane proteins: trafficking meets function. Nat. Rev. Mol. Cell Biol. 10, 623–635 (2009).
Luzio, J. P., Parkinson, M. D., Gray, S. R. & Bright, N. A. The delivery of endocytosed cargo to lysosomes. Biochem. Soc. Trans. 37, 1019–1021 (2009).
Mizushima, N., Levine, B., Cuervo, A. M. & Klionsky, D. J. Autophagy fights disease through cellular self-digestion. Nature 451, 1069–1075 (2008).
Kaushik, S. & Cuervo, A. M. Chaperone-mediated autophagy: a unique way to enter the lysosome world. Trends Cell Biol. 22, 407–417 (2012).
Bao, W. et al. Toll-like receptor 9 can be activated by endogenous mitochondrial DNA to induce podocyte apoptosis. Sci. Rep. 6, 22579 (2016).
Kawai, T. & Akira, S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat. Immunol. 11, 373–384 (2010).
Choi, S., Thapa, N., Tan, X., Hedman, A. C. & Anderson, R. A. PIP kinases define PI4,5P2 signaling specificity by association with effectors. Biochim. Biophys. Acta 1851, 711–723 (2015).
Itakura, E., Kishi-Itakura, C. & Mizushima, N. The hairpin-type tail-anchored SNARE syntaxin 17 targets to autophagosomes for fusion with endosomes/lysosomes. Cell 151, 1256–1269 (2012).
Dong, X. P. et al. PI(3,5)P2 controls membrane trafficking by direct activation of mucolipin Ca2+ release channels in the endolysosome. Nat. Commun. 1, 38 (2010).
Zhang, X., Li, X. & Xu, H. Phosphoinositide isoforms determine compartment-specific ion channel activity. Proc. Natl Acad. Sci. USA 109, 11384–11389 (2012).
Vergarajauregui, S., Connelly, P. S., Daniels, M. P. & Puertollano, R. Autophagic dysfunction in mucolipidosis type IV patients. Hum. Mol. Genet. 17, 2723–2737 (2008).
Kimura, T. et al. Autophagy protects the proximal tubule from degeneration and acute ischemic injury. J. Am. Soc. Nephrol. 22, 902–913 (2011).
Dressman, M. A., Olivos-Glander, I. M., Nussbaum, R. L. & Suchy, S. F. Ocrl1, a PtdIns(4,5)P2 5-phosphatase, is localized to the trans-Golgi network of fibroblasts and epithelial cells. J. Histochem. Cytochem. 48, 179–190 (2000).
Olivos-Glander, I. M., Janne, P. A. & Nussbaum, R. L. The oculocerebrorenal syndrome gene product is a 105-kD protein localized to the Golgi complex. Am. J. Hum. Genet. 57, 817–823 (1995).
van Rahden, V. A. et al. The 5-phosphatase OCRL mediates retrograde transport of the mannose 6-phosphate receptor by regulating a Rac1-cofilin signalling module. Hum. Mol. Genet. 21, 5019–5038 (2012).
Braulke, T. & Bonifacino, J. S. Sorting of lysosomal proteins. Biochim. Biophys. Acta 1793, 605–614 (2009).
Noakes, C. J., Lee, G. & Lowe, M. The PH domain proteins IPIP27A and B link OCRL1 to receptor recycling in the endocytic pathway. Mol. Biol. Cell 22, 606–623 (2011).
Billcliff, P. G. et al. OCRL1 engages with the F-BAR protein pacsin 2 to promote biogenesis of membrane-trafficking intermediates. Mol. Biol. Cell 27, 90–107 (2016).
Raghavan, V. & Weisz, O. A. Flow stimulated endocytosis in the proximal tubule. Curr. Opin. Nephrol. Hypertens. 24, 359–365 (2015).
Satir, P., Pedersen, L. B. & Christensen, S. T. The primary cilium at a glance. J. Cell Sci. 123, 499–503 (2010).
Goetz, S. C. & Anderson, K. V. The primary cilium: a signalling centre during vertebrate development. Nat. Rev. Genet. 11, 331–344 (2010).
Knodler, A. et al. Coordination of Rab8 and Rab11 in primary ciliogenesis. Proc. Natl Acad. Sci. USA 107, 6346–6351 (2010).
Kaplan, O. I. et al. Endocytosis genes facilitate protein and membrane transport in C. elegans sensory cilia. Curr. Biol. 22, 451–460 (2012).
Luo, N. et al. Primary cilia signaling mediates intraocular pressure sensation. Proc. Natl Acad. Sci. USA 111, 12871–12876 (2014).
Luo, N. et al. OCRL localizes to the primary cilium: a new role for cilia in Lowe syndrome. Hum. Mol. Genet. 21, 3333–3344 (2012).
Nachury, M. V. et al. A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis. Cell 129, 1201–1213 (2007).
Rbaibi, Y. et al. OCRL1 modulates cilia length in renal epithelial cells. Traffic 13, 1295–1305 (2012).
Luo, N. et al. Compensatory role of inositol 5-phosphatase INPP5B to OCRL in primary cilia formation in oculocerebrorenal syndrome of Lowe. PLoS ONE 8, e66727 (2013).
Janne, P. A. et al. Functional overlap between murine Inpp5b and Ocrl1 may explain why deficiency of the murine ortholog for OCRL1 does not cause Lowe syndrome in mice. J. Clin. Invest. 101, 2042–2053 (1998).
Matzaris, M. et al. Distinct membrane and cytosolic forms of inositol polyphosphate 5-phosphatase II. Efficient membrane localization requires two discrete domains. J. Biol. Chem. 273, 8256–8267 (1998).
Erdmann, K. S. et al. A role of the Lowe syndrome protein OCRL in early steps of the endocytic pathway. Dev. Cell 13, 377–390 (2007).
Williams, C., Choudhury, R., McKenzie, E. & Lowe, M. Targeting of the type II inositol polyphosphate 5-phosphatase INPP5B to the early secretory pathway. J. Cell Sci. 120, 3941–3951 (2007).
Bothwell, S. P., Farber, L. W., Hoagland, A. & Nussbaum, R. L. Species-specific difference in expression and splice-site choice in Inpp5b, an inositol polyphosphate 5-phosphatase paralogous to the enzyme deficient in Lowe syndrome. Mamm. Genome 21, 458–466 (2010).
Bothwell, S. P. et al. Mouse model for Lowe syndrome/Dent disease 2 renal tubulopathy. J. Am. Soc. Nephrol. 22, 443–448 (2011).
Inoue, K. et al. Kidney tubular ablation of Ocrl/Inpp5b phenocopies Lowe syndrome tubulopathy. J. Am. Soc. Nephrol. 28, 1399–1407 (2017).
Loovers, H. M. et al. Regulation of phagocytosis in Dictyostelium by the inositol 5-phosphatase OCRL homolog Dd5P4. Traffic 8, 618–628 (2007).
Lowe, M. Structure and function of the Lowe syndrome protein OCRL1. Traffic 6, 711–719 (2005).
Ramirez, I. B. et al. Impaired neural development in a zebrafish model for Lowe syndrome. Hum. Mol. Genet. 21, 1744–1759 (2012).
Oltrabella, F. et al. The Lowe syndrome protein OCRL1 is required for endocytosis in the zebrafish pronephric tubule. PLoS Genet. 11, e1005058 (2015).
Nielsen, R. et al. Endocytosis provides a major alternative pathway for lysosomal biogenesis in kidney proximal tubular cells. Proc. Natl Acad. Sci. USA 104, 5407–5412 (2007).
Sagona, A. P., Nezis, I. P. & Stenmark, H. Association of CHMP4B and autophagy with micronuclei: implications for cataract formation. Biomed Res. Int. 2014, 974393 (2014).
Morishita, H. & Mizushima, N. Autophagy in the lens. Exp. Eye Res. 144, 22–28 (2016).
Ivanova, E. A. et al. Endo-lysosomal dysfunction in human proximal tubular epithelial cells deficient for lysosomal cystine transporter cystinosin. PLoS ONE 10, e0120998 (2015).
Cherqui, S. & Courtoy, P. J. The renal Fanconi syndrome in cystinosis: pathogenic insights and therapeutic perspectives. Nat. Rev. Nephrol. 13, 115–131 (2017).
Gabriel, S. S. et al. Bone marrow transplantation improves proximal tubule dysfunction in a mouse model of Dent disease. Kidney Int. 91, 842–855 (2017).
Rendu, J. et al. Functional characterization and rescue of a deep intronic mutation in OCRL gene responsible for Lowe syndrome. Hum. Mutat. 38, 152–159 (2017).
McCrea, H. J. et al. All known patient mutations in the ASH-RhoGAP domains of OCRL affect targeting and APPL1 binding. Biochem. Biophys. Res. Commun. 369, 493–499 (2008).
Swan, L. E., 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. USA 107, 3511–3516 (2010).
Jefferson, A. B., Auethavekiat, V., Pot, D. A., Williams, L. T. & Majerus, P. W. Signaling inositol polyphosphate-5-phosphatase. Characterization of activity and effect of GRB2 association. J. Biol. Chem. 272, 5983–5988 (1997).
Bascom, R. A., Srinivasan, S. & Nussbaum, R. L. Identification and characterization of golgin-84, a novel Golgi integral membrane protein with a cytoplasmic coiled-coil domain. J. Biol. Chem. 274, 2953–2962 (1999).
Abdelmohsen, K. et al. Ubiquitin-mediated proteolysis of HuR by heat shock. EMBO J. 28, 1271–1282 (2009).
Castello, A. et al. Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 149, 1393–1406 (2012).
Huttlin, E. L. et al. The BioPlex Network: a systematic exploration of the human interactome. Cell 162, 425–440 (2015).
Emdal, K. B. et al. Temporal proteomics of NGF-TrkA signaling identifies an inhibitory role for the E3 ligase Cbl-b in neuroblastoma cell differentiation. Sci. Signal. 8, ra40 (2015).
Galligan, J. T. et al. Proteomic analysis and identification of cellular interactors of the giant ubiquitin ligase HERC2. J. Proteome Res. 14, 953–966 (2015).
Gupta, G. D. et al. A dynamic protein interaction landscape of the human centrosome-cilium interface. Cell 163, 1484–1499 (2015).
Kirli, K. et al. A deep proteomics perspective on CRM1-mediated nuclear export and nucleocytoplasmic partitioning. eLife 4, e11466 (2015).
Hein, M. Y. et al. A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 163, 712–723 (2015).
Acknowledgements
We thank Cathal Wilson, Telethon Institute of Genetics and Medicine, Italy, for critical reading of the manuscript. M.A.D.M. acknowledges the support of Telethon (grant TGM11CB1), European Research Council Advanced Investigator grant no. 670881 (SYSMET), Associazione Italiana Sindrome di Lowe (AISLO). O.D. acknowledges the European Community's Seventh Framework Programme under grant agreement n° 305608 (EURenOmics), the Cystinosis Research Foundation (Irvine, California, USA), the Swiss National Science Foundation (project grant 31003A-169850), the clinical research priority program (KFSP) radiz (Rare Disease Initiative Zurich) of the UZH.
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Glossary
- Lysosomes
-
Membrane-bound organelles that contain degradative enzymes. They are the terminal station of the endocytic pathway.
- Clathrin
-
A protein that assembles into a coat and is recruited via adaptor complexes to selective plasma membrane proteins that have to be internalized.
- Coated pits
-
Invaginations on the plasma membrane where clathrin-mediated endocytosis initiates.
- Apical endosomal compartment
-
Early endosomes localized in the apical zone of polarized cells.
- Early endosomes
-
The first membrane-bound organelles that receive material from endocytic vesicles and are identified by the small GTPase Rab5. Early endosomes are an important sorting station and undergo maturation into late endosomes through a process that involves acidification and switching of the associated Rab GTPase, involving loss of Rab5 and acquisition of Rab7.
- Late endosomes
-
Membrane-bound organelles, positive for Rab7, that undergo fusion with lysosomes.
- Autophagic flux
-
Autophagic flux involves the formation of autophagosomes that encapsulate the material to be degraded and culminates in the fusion of autophagosomes with lysosomes.
- Balanced X chromosome:autosome translocation
-
The even exchange of genetic material between the X chromosome and an autosome, ideally with no loss of information.
- Nonrandom X chromosome inactivation
-
X inactivation is in general random (that is, there is an even ratio between paternal or maternal X inactivation). In nonrandom X chromosome inactivation the ratio of inactivation between the paternal or maternal X chromosome is skewed towards one of them.
- Buphthalmos
-
Enlargement of the eye-bulb due to increased intraocular pressure.
- Microphthalmos
-
Small eyes compared to those of healthy individuals.
- Enophthalmos
-
Posterior dysplacement of the eye within the orbit.
- Nystagmus
-
Involuntary eye movements resulting in reduced visual acuity.
- Scoliosis
-
Medical condition where the spine curves to the side.
- Plasma membrane ruffles
-
Plasma membrane domains that undergo actin-driven rapid reorganization.
- Actin comets
-
Structures generated by dynamic polymerization of actin on the surface of membrane vesicles or bacteria.
- Pseudopod extension
-
Transient extension of portions of plasma membrane involved in cell motility and phagocytosis.
- Lysosome cargo response
-
Signalling cascade triggered at the lysosomes by the arrival of autophagic cargo.
- SNARE protein
-
Proteins that mediate membrane fusion.
- Basal body
-
Centrioles located at the base of the primary cilium that are involved in the nucleation of microtubules within the cilium.
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De Matteis, M., Staiano, L., Emma, F. et al. The 5-phosphatase OCRL in Lowe syndrome and Dent disease 2. Nat Rev Nephrol 13, 455–470 (2017). https://doi.org/10.1038/nrneph.2017.83
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DOI: https://doi.org/10.1038/nrneph.2017.83
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