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

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 OCRL1, an inositol polyphosphate 5-phosphatase that dephosphorylates PI(4,5)P2, 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 poorly understood. Here we demonstrate that cilia from Lowe syndrome patient fibroblasts exhibit increased levels of PI(4,5)P2 and decreased levels of PI4P. In particular, subcellular distribution of PI(4,5)P2 build-up was observed at the transition zone. Accumulation of ciliary PI(4,5)P2 was pronounced in mouse embryonic fibroblasts (MEFs) derived from Lowe syndrome mouse model as well as in Ocrl null MEFs, which was reversed by reintroduction of OCRL. Similarly, expression of wildtype OCRL reversed the elevated PI(4,5)P2 in Lowe patient cells. Sonic hedgehog accumulation in response to hedgehog agonist was decreased in MEFs derived from Lowe syndrome mouse model. Together, our findings for the first time show an abnormality in ciliary phosphoinositides of both human and mouse cell models of Lowe syndrome.