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

<div><p>Inositol phosphatases are important regulators of cell signaling, polarity, and vesicular trafficking. Mutations in <i>OCRL</i>, 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. <i>INPP5B</i> is a paralog of <i>OCRL</i> and shares similar structural domains. The roles of <i>OCRL</i> and <i>INPP5B</i> 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 <i>INPP5B</i>. This is further supported by the defective cilia formation in zebrafish Kupffer’s vesicles and in cilia-dependent melanosome transport assays in <i>inpp5b</i> morphants. Taken together, this study indicates that <i>OCRL</i> and <i>INPP5B</i> are differentially expressed in the human and murine eyes, and play compensatory roles in cilia development.</p>