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Loss of OCRL increases ciliary PI(4,5)P2 in Lowe oculocerebrorenal syndrome.
J Cell Sci 2017; 130(20):3447-3454JC

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)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 is 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 wild-type OCRL reversed the elevated PI(4,5)P2 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.

Authors+Show Affiliations

Stanford University, Department of Ophthalmology, 1651 Page Mill Road, Rm 2220, Palo Alto, CA 94304, USA.Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.Stanford University, Department of Ophthalmology, 1651 Page Mill Road, Rm 2220, Palo Alto, CA 94304, USA.Stanford University, Department of Ophthalmology, 1651 Page Mill Road, Rm 2220, Palo Alto, CA 94304, USA.Stanford University, Department of Ophthalmology, 1651 Page Mill Road, Rm 2220, Palo Alto, CA 94304, USA.Stanford University, Department of Ophthalmology, 1651 Page Mill Road, Rm 2220, Palo Alto, CA 94304, USA yangsun@stanford.edu. Palo Alto Veterans Administration, Palo Alto, CA 94304, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28871046

Citation

Prosseda, Philipp P., et al. "Loss of OCRL Increases Ciliary PI(4,5)P2 in Lowe Oculocerebrorenal Syndrome." Journal of Cell Science, vol. 130, no. 20, 2017, pp. 3447-3454.
Prosseda PP, Luo N, Wang B, et al. Loss of OCRL increases ciliary PI(4,5)P2 in Lowe oculocerebrorenal syndrome. J Cell Sci. 2017;130(20):3447-3454.
Prosseda, P. P., Luo, N., Wang, B., Alvarado, J. A., Hu, Y., & Sun, Y. (2017). Loss of OCRL increases ciliary PI(4,5)P2 in Lowe oculocerebrorenal syndrome. Journal of Cell Science, 130(20), pp. 3447-3454. doi:10.1242/jcs.200857.
Prosseda PP, et al. Loss of OCRL Increases Ciliary PI(4,5)P2 in Lowe Oculocerebrorenal Syndrome. J Cell Sci. 2017 Oct 15;130(20):3447-3454. PubMed PMID: 28871046.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Loss of OCRL increases ciliary PI(4,5)P2 in Lowe oculocerebrorenal syndrome. AU - Prosseda,Philipp P, AU - Luo,Na, AU - Wang,Biao, AU - Alvarado,Jorge A, AU - Hu,Yang, AU - Sun,Yang, Y1 - 2017/09/04/ PY - 2016/12/20/received PY - 2017/08/29/accepted PY - 2017/9/6/pubmed PY - 2018/6/8/medline PY - 2017/9/6/entrez KW - Lowe syndrome KW - OCRL KW - PI(4,5)P2 KW - Phosphoinositide KW - Primary cilia KW - Sonic hedgehog SP - 3447 EP - 3454 JF - Journal of cell science JO - J. Cell. Sci. VL - 130 IS - 20 N2 - 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)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 is 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 wild-type OCRL reversed the elevated PI(4,5)P2 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. SN - 1477-9137 UR - https://www.unboundmedicine.com/medline/citation/28871046/Loss_of_OCRL_increases_ciliary_PI_45_P2_in_Lowe_oculocerebrorenal_syndrome_ L2 - http://jcs.biologists.org/cgi/pmidlookup?view=long&pmid=28871046 DB - PRIME DP - Unbound Medicine ER -