The Cellular and Physiological Functions of the Lowe Syndrome Protein OCRL1

Abstract

Phosphoinositide lipids play a key role in cellular physiology, participating in a wide array of cellular processes. Consequently, mutation of phosphoinositide-metabolizing enzymes is responsible for a growing number of diseases in humans. Two related disorders, oculocerebrorenal syndrome of Lowe (OCRL) and Dent-2 disease, are caused by mutation of the inositol 5-phosphatase OCRL1. Here, we review recent advances in our understanding of OCRL1 function. OCRL1 appears to regulate many processes within the cell, most of which depend upon coordination of membrane dynamics with remodeling of the actin cytoskeleton. Recently developed animal models have managed to recapitulate features of Lowe syndrome and Dent-2 disease, and revealed new insights into the underlying mechanisms of these disorders. The continued use of both cell-based approaches and animal models will be key to fully unraveling OCRL1 function, how its loss leads to disease and, importantly, the development of therapeutics to treat patients.

Primary cilia signaling mediates intraocular pressure sensation

“…OCRL is an inositol polyphosphate 5-phosphatase that is implicated in Lowe syndrome and Dent disease (1,45,46). The recent discovery of its localization to cilia suggested its potential role in the pathophysiology of glaucoma in the TM of eyes (4,6,7).…”

PIP2Clustering: From model membranes to cells

“…This is irreversible, and PIP2 turned over by PLC must be replaced by the slow process of new PI synthesis in the ER, phosphorylation, and plasma membrane delivery. Alternatively, the 5 0 phosphate can be cleaved from PIP2 by any of several phosphatases (ten in mammals and four in S. cerevisiae) to generate PI(4)P (Ooms et al, 2009;Mehta et al, 2014). Thus, balanced activity of appropriate PIP5KI and 5 0 phosphatase proteins provides a rapid and flexible mechanism for fine-tuning local PIP2 levels in specific plasma membrane sites.…”

Dent's disease complicated by nephrotic syndrome: A case report

“…In Dent's disease, however, proteinuria is mainly LMWP. LMWP is a result of tubular dysfunction that prevents effective reabsorption of low-molecular-weight proteins, including α1 and β2 microglobulins, retinol-binding protein (RBP), Clara cell protein, and vitamin D binding protein, that are filtered through the glomerular basement membrane (10)(11)(12). However, albuminuria will be produced when there are defects in the glomerular basement membrane.…”