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Official Full Name
oculocerebrorenal syndrome of Lowe
Background
This gene encodes a phosphatase enzyme that is involved in actin polymerization and is found in the trans-Golgi network. Mutations in this gene cause oculocerebrorenal syndrome of Lowe and also Dent disease.
Synonyms
OCRL; oculocerebrorenal syndrome of Lowe; inositol polyphosphate 5-phosphatase OCRL-1; OCRL1; Lowe oculocerebrorenal syndrome protein; phosphatidylinositol polyphosphate 5-phosphatase; LOCR; NPHL2; INPP5F; OCRL-1; wu:fi09g03; zgc:152864

The gene and protein domains

OCRL is one of ten inositol polyphosphate 5‑phosphatases present in eukaryotic cells and is encoded by a 23 exon-containing gene located on chromosome Xq 25–26. It exists in two isoforms: the a isoform is ubiquitously expressed, however, the b isoform is expressed in all tissues other than the brain. OCRL is a multi-domain protein of 110 kDa (Figure 1). In addition to its 5‑phosphatase catalytic domain, it contains a pleckstrin homology (PH domain (which, unlike PH domains of other proteins, is unable to bind phosphoinositides), an ASPM, Hydin (ASH) domain, SPD‑2, characteristic of proteins that localize to centrosomes and primary cilia, and a RhoGAP-like domain, which does not, nevertheless, exhibit any GTPase activating function but instead mediates the interaction of OCRL with Rac1 and Cdc42.

Figure 1. Organization of domains in the full-length OCRL protein.

The cellular roles of OCRL

OCRL contains multiple and specific protein binding motifs, including two clathrin binding motifs (one in a loop inserted in the PH domain of the a isoform of OCRL and one in the Rho GAP-like domain), a Rab-binding site in the ASH domain, an AP2‑interacting motif, and a site which binds the endocytic proteins APPL1 and IPIP27A and IPIP27B (also known as Ses1 and Ses2). These motifs enable OCRL to interact with a wide array of proteins, which mostly facilitate its targeting to different cell compartments. OCRL can localize to the plasma membrane, early endosomes, clathrin-coated pits, clathrin-coated vesicles, the trans-Golgi network, the primary cilium and to lysosomes (Figure 2).

Figure 2. Intracellular distribution of OCRL in proximal tubular cells.

Of the proteins that interact with OCRL, the Rab GTPases are the most numerous and are responsible for the localization of OCRL to different cell compartments. OCRL targets endosomes, the Golgi complex and primary cilium through its interactions with Rab1, Rab5, Rab6, Rab8 and Rab35. By binding to Rab35, OCRL can be also targeted to the intracellular bridge in dividing cells where it controls cytokinesis.

The CCRL mutations and disease

Lowe syndrome is an X‑linked disease which is characterized by congenital cataracts, intellectual disability, central hypotonia, and renal Fanconi syndrome. The disease is caused by mutations in OCRL, which encodes an inositol polyphosphate 5‑phosphatase that acts on phosphoinositides — quantitatively minor constituents of cell membranes that are nonetheless pivotal regulators of intracellular trafficking. And Dent disease is an X‑linked proximal tubulopathy characterized by low molecular-weight proteinuria, hypercalciuria, and progressive renal failure. The disease was initially identified as being caused by mutations in CLCN5, which encodes the ClC‑5 endosomal chloride channel. Whereas mutations in this gene could not be identified in a substantial proportion of patients, and subsequent studies showed that mutations in OCRL are responsible for approximately 15% of cases. Patients with mutations in OCRL are defined as having Dent disease 2 to distinguish them from the more frequent Dent disease 1, which is caused by CLCN5 mutations.

Pathogenic mutations in OCRL can occur throughout the gene. However, nearly all mutations associated with Lowe syndrome are located in exons 8–23, which comprises the inositol polyphosphate 5‑phosphatase, ASH and RhoGAP-like domains, whereas the majority of mutations that cause Dent disease 2 are located in exons 1–7, which encompass the PH domain. The severity of the clinical phenotype of patients with Lowe syndrome and Dent disease 2 can vary considerably, even between patients with mutations that are predicted to cause complete loss of function of the protein or between patients who share the same mutation, suggesting that genetic background might influence the clinical expression of the disease.

Drug targets in Lowe syndrome

The major challenge will be to identify avenues for the treatment of Lowe syndrome in the next few years. Different strategies are theoretically feasible, ranging from OCRL replacement via gene therapy or hematopoietic stem cell transplantation, to exon-skipping therapy for selected mutations or the identification of targets that are amenable to pharmacological manipulation. The identification of druggable targets to treat Lowe syndrome is a viable option: OCRL is a phosphatase and many of the phenotypes caused by loss of function of OCRL result from the accumulation of its substrate, PI(4,5)P2. Moreover, a number of independent studies in cellular systems have shown that depletion of phosphoinositide kinases (either PIP5K or PI4K) can mitigate the accumulation of PI(4,5)P2 in OCRL-depleted cells and rescue some of the phenotypes linked to the loss of OCRL. Therefore, the development of selective, small molecule PIP5K inhibitors could enable PI(4,5)P2 balance to be restored in patients with Lowe syndrome.

References:

  1. Pirruccello M, De C P. Inositol 5-phosphatases: insights from the Lowe syndrome protein OCRL. Trends in Biochemical Sciences, 2012, 37(4):134-143.
  2. Sharma S, et al. The role of the Lowe syndrome protein OCRL in the endocytic pathway. Biological Chemistry, 2015, 396(12):1293-1300.
  3. De Matteis M A, et al. The 5-phosphatase OCRL in Lowe syndrome and Dent disease 2. Nature Reviews Nephrology, 2017, 13(8):455.
  4. Rendu J, et al. Functional Characterization and Rescue of a Deep Intronic Mutation in OCRL Gene Responsible for Lowe Syndrome. Human Mutation, 2017, 38(2).
  5. Coon B G, et al. The Lowe syndrome protein OCRL1 is involved in primary cilia assembly. Human Molecular Genetics, 2012, 21(6):1835-47.
  6. Vicinanza M, et al. OCRL controls trafficking through early endosomes via PtdIns4,5P₂-dependent regulation of endosomal actin. Embo Journal, 2014, 30(24):4970-4985.