Compensatory Role of Inositol 5-Phosphatase INPP5B to OCRL in Primary Cilia Formation in Oculocerebrorenal Syndrome of Lowe.

Na Luo,Ryan Anderson,Michael Conwell,Yang Sun,Robert N Weinreb,Akhilesh Kumar,Sudipto Roy

doi:10.1371/journal.pone.0066727

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.

Highlights

Oculocerebrorenal syndrome of Lowe (MIM #309000) is an Xlinked recessive disorder characterized by the presence of congenital cataracts, glaucoma, mental retardation, and renal dysfunction [1,2,3]
Glaucoma development in the Lowe syndrome patients represent a form of trabeculodysgenesis, which is the abnormal development of the trabecular meshwork that regulates aqueous humor outflow from the eye [4]
OCRL mutations have been found in Lowe syndrome, which usually presents with bilateral congenital cataracts and glaucoma [4]; the pathogenesis of these ocular phenotypes is not known

Summary

Introduction

Oculocerebrorenal syndrome of Lowe (MIM #309000) is an Xlinked recessive disorder characterized by the presence of congenital cataracts, glaucoma, mental retardation, and renal dysfunction [1,2,3]. Lowe syndrome results from mutations in OCRL, a type II inositol polyphosphate 5-phosphatase [2]. Patients with Lowe syndrome typically present with bilateral congenital discoid cataracts, which may be caused by disorganization of embryonic lens epithelium [4,5]. Glaucoma is present in approximately 47% (44 of 93) of Lowe syndrome patients [4]. Glaucoma development in the Lowe syndrome patients represent a form of trabeculodysgenesis, which is the abnormal development of the trabecular meshwork that regulates aqueous humor outflow from the eye [4]. 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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Results

Conclusion