Loss of OCRL increases ciliary PI(4,5)P2 in Lowe oculocerebrorenal syndrome

Abstract

Lowe syndrome is a rare X-linked disorder characterized by bilateral congenital cataracts and glaucoma, mental retardation, and proximal renal tubular dysfunction. Mutations in OCRL, an inositol polyphosphate 5-phosphatase that dephosphorylates PI(4,5)P, cause Lowe syndrome. Previously we showed that OCRL localizes to the primary cilium, which has a distinct membrane phospholipid composition, but disruption of phosphoinositides in the ciliary membrane is poorly understood. Here, we demonstrate that cilia from Lowe syndrome patient fibroblasts exhibit increased levels of PI(4,5)P and decreased levels of PI4P. In particular, subcellular distribution of PI(4,5)P build-up was observed at the transition zone. Accumulation of ciliary PI(4,5)P was pronounced in mouse embryonic fibroblasts (MEFs) derived from Lowe syndrome mouse model as well as in -null MEFs, which was reversed by reintroduction of OCRL. Similarly, expression of wild-type OCRL reversed the elevated PI(4,5)P in Lowe patient cells. Accumulation of sonic hedgehog protein in response to hedgehog agonist was decreased in MEFs derived from a Lowe syndrome mouse model. Together, our findings show for the first time an abnormality in ciliary phosphoinositides of both human and mouse cell models of Lowe syndrome.

The impact of phosphoinositide 5-phosphatases on phosphoinositides in cell function and human disease

“…OCRL is described as a PI(4,5)P 2 5-phosphatase (Table 1), and PI(4,5)P 2 levels have been shown to be very much increased in cell lines from kidney proximal tubules of a patient with Lowe syndrome compared with controls (46). OCRL localizes to the primary cilium and cilia from Lowe-patient fibroblasts, where it exhibits increased levels of PI(4,5)P 2 (47). SHIP2 also controls plasma membrane PI(4,5)P 2 , thereby participating in the control of cell migration in 1321 N1 glioblastoma cells (48).…”

Occludin knockdown is not sufficient to induce transepithelial macromolecule passage

“…20 With no indication of a direct effect on permeability, occludin was reported to regulate TJs and/or TJ assembly 21 and disassembly of the apical junctional complex, 22 as well as lumen formation in 3D-culture. 23 Based on studies in different epithelial cells, occludin seems to play a role in epithelial wound healing, 24 apoptosis 25 and to be important to the interaction with intraepithelial lymphocytes. 26 Studies addressing occludin's role in barrier function have suggested involvement in serine proteasedependent barrier modulation, 27 hypoxia-induced, 28 ethanol-induced 29 and hydrogen peroxideinduced reduction in barrier function.…”

Mutations In PIK3C2A Cause Syndromic Short Stature, Skeletal Abnormalities, and Cataracts Associated With Ciliary Dysfunction

“…It is intriguing that both PIK3C2A and OCRL have important roles in primary cilia formation (Franco et al, 2014;Luo et al, 2012;Prosseda et al, 2017). Primary cilia are evolutionary conserved microtubule-derived cellular organelles that protrude from the surface of most mammalian cell types.…”