From Lowe Syndrome to Dent Disease: Correlations between Mutations of the OCRL1 Gene and Clinical and Biochemical Phenotypes

CHU Grenoble, Laboratoire de Biochimie et Génétique Moléculaire, Grenoble, France.
Human Mutation (Impact Factor: 5.14). 04/2011; 32(4):379-88. DOI: 10.1002/humu.21391
Source: PubMed


Mutations of OCRL1 are associated with both the Lowe oculocerebrorenal syndrome, a multisystemic and Dent-2 disease, a renal tubulopathy. We have identified a mutation in 130 Lowe syndrome families and 6 affected by Dent-2 disease with 51 of these mutations being novel. No founding effect was evidenced for recurrent mutations. Two mutations initially reported as causing Dent-2 disease were identified in patients, including two brothers, presenting with Lowe syndrome thus extending the clinical variability of OCRL1 mutations. mRNA levels, protein content, and PiP(2) -ase activities were analyzed in patient's fibroblasts. Although mRNA levels were normal in cells harboring a missense mutation, the OCRL1 content was markedly lowered, suggesting that enzymatic deficiency resulted mainly from protein degradation rather than from a catalytic inactivation. Analysis of a splicing mutation that led to the elimination of the initiation codon evidenced the presence of shortened forms of OCRL1 that might result from the use of alternative initiation codons. The specific mapping of the frameshift and nonsense mutations, exclusively identified in exons 1-7 and exons 8-23, respectively, for Dent disease and Lowe syndrome together with the possible use of alternative initiation codons might be related to their clinical expression, that is, Lowe syndrome or Dent-2 disease.

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    • "Produced by the nonpigmented layer of epithelial cells (NPCE) in the ciliary body, the major route of aqueous humor drainage is via the trabecular meshwork and then into the Schlemm’s canal, a monolayer of endothelial cells, where it finally drains out of the eye by joining the venous blood vessels [6]. Over 208 mutations in OCRL have been described with a wide range of phenotypes that involve multiple organ systems [7]. However, very little is known how defects in OCRL results in cellular dysfunction that underlies cataracts formation and the defective flow of aqueous humor that leads to congenital glaucoma. "
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    ABSTRACT: Inositol phosphatases are important regulators of cell signaling, polarity, and vesicular trafficking. Mutations in OCRL, an inositol polyphosphate 5-phosphatase, result in Oculocerebrorenal syndrome of Lowe, an X-linked recessive disorder that presents with congenital cataracts, glaucoma, renal dysfunction and mental retardation. INPP5B is a paralog of OCRL and shares similar structural domains. The roles of OCRL and INPP5B in the development of cataracts and glaucoma are not understood. Using ocular tissues, this study finds low levels of INPP5B present in human trabecular meshwork but high levels in murine trabecular meshwork. In contrast, OCRL is localized in the trabecular meshwork and Schlemm's canal endothelial cells in both human and murine eyes. In cultured human retinal pigmented epithelial cells, INPP5B was observed in the primary cilia. A functional role for INPP5B is revealed by defects in cilia formation in cells with silenced expression of INPP5B. This is further supported by the defective cilia formation in zebrafish Kupffer's vesicles and in cilia-dependent melanosome transport assays in inpp5b morphants. Taken together, this study indicates that OCRL and INPP5B are differentially expressed in the human and murine eyes, and play compensatory roles in cilia development.
    Full-text · Article · Jun 2013 · PLoS ONE
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    • "It has also been speculated that the use of alternative initiation codons (methionine at position 158, 187, and 206) in exons 7 and 8 will allow the synthesis of truncated OCRL proteins. Indeed, Hichri et al. (2011) have detected two smaller proteins (around 80 kDa) instead of the 104 kDa full-length protein in a Dent 2 case lacking the normal initiator ATG in exon 1. Hence, some residual activity of these smaller products might contribute to the phenotypic differences observed. "

    Full-text · Chapter · Mar 2012
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    • "Many Lowe syndrome causing amino-acid substitutions are localized in the 5-phosphatase domain of OCRL1, suggesting that impairment of catalytic activity is part of the OCRL1 disease mechanism (Hichri et al, 2010). "
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    ABSTRACT: The oculocerebrorenal syndrome of Lowe (OCRL), also called Lowe syndrome, is characterized by defects of the nervous system, the eye and the kidney. Lowe syndrome is a monogenetic X-linked disease caused by mutations of the inositol-5-phosphatase OCRL1. OCRL1 is a membrane-bound protein recruited to membranes via interaction with a variety of Rab proteins. The structural and kinetic basis of OCRL1 for the recognition of several Rab proteins is unknown. In this study, we report the crystal structure of the Rab-binding domain (RBD) of OCRL1 in complex with Rab8a and the kinetic binding analysis of OCRL1 with several Rab GTPases (Rab1b, Rab5a, Rab6a and Rab8a). In contrast to other effectors that bind their respective Rab predominantly via α-helical structure elements, the Rab-binding interface of OCRL1 consists mainly of the IgG-like β-strand structure of the ASPM-SPD-2-Hydin domain as well as one α-helix. Our results give a deeper structural understanding of disease-causing mutations of OCRL1 affecting Rab binding.
    Full-text · Article · Mar 2011 · The EMBO Journal
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