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  • Review Article
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The 5-phosphatase OCRL in Lowe syndrome and Dent disease 2

Key Points

  • 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

  • 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

  • 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

  • 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

  • Mouse and zebrafish animal models of Lowe syndrome are available, but these do not fully recapitulate the manifestations of Lowe syndrome

  • 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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Figure 1: The endolysosomal pathway in proximal tubular cells and the disease genes that cause renal Fanconi syndrome.
Figure 2: The cycle and subcellular distribution of phosphoinositides and Rab GTPases.
Figure 3: The genomic organization and protein architecture of OCRL.
Figure 4: Intracellular distribution and compartment-specific interactome of OCRL in proximal tubular cells.
Figure 5: Cellular alterations that result from dysfunctional OCRL.

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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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