March 2012
Volume 53, Issue 14
Free
ARVO Annual Meeting Abstract  |   March 2012
Oculocerebral Renal Syndrome of Lowe: the Role of Ocrl in Primary Cilia Development
Author Affiliations & Notes
  • Yang Sun
    Department of Ophthalmology, Ophthalmology,
    Indiana University, indianapolis, Indiana
  • Na Luo
    Department of Ophthalmology, Ophthalmology,
    Indiana University, indianapolis, Indiana
  • Callah West
    Indiana University, Indianapolis, Indiana
  • Luo Sun
    Department of Ophthalmology, Ophthalmology,
    Indiana University, Indianapolis, Indiana
  • Carlos Murga Zamalloa
    Department of Pathology, University of Michigan, Ann Arbor, Michigan
  • Hemant Khanna
    Ophthalmology, University of Massachusetts Medical School, Worcester, Massachusetts
  • Jeffrey Travers
    Department of Dermatology,
    Indiana University, indianapolis, Indiana
  • Footnotes
    Commercial Relationships  Yang Sun, None; Na Luo, None; Callah West, None; Luo Sun, None; Carlos Murga Zamalloa, None; Hemant Khanna, None; Jeffrey Travers, None
  • Footnotes
    Support  Knights Templar Eye Foundation, American Glaucoma Society
Investigative Ophthalmology & Visual Science March 2012, Vol.53, 3835. doi:
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      Yang Sun, Na Luo, Callah West, Luo Sun, Carlos Murga Zamalloa, Hemant Khanna, Jeffrey Travers; Oculocerebral Renal Syndrome of Lowe: the Role of Ocrl in Primary Cilia Development. Invest. Ophthalmol. Vis. Sci. 2012;53(14):3835.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : Lowe Syndrome (Oculocerebral renal syndrome; MIM#309000) is an X-linked disorder characterized by congenital glaucoma, cataract, renal dysfunction, and mental retardation. The defective gene in Lowe syndrome is Ocrl, an inositol polyphosphate 5-phosphatase. The purpose of this study is to investigate the role of Ocrl in the pathogenesis of the ocular phenotypes of Lowe syndrome.

Methods: : Immunofluorescence and live-cell microscopy of primary and transformed human trabecular meshwork (HTM) and retinal pigmented epithelial (RPE) cells were performed. Knockdown of Ocrl in HTM and RPE in cell lines was performed using specific plko.1 shRNA as described (Feng, Y. Genomics Proteomics 2010).

Results: : Endogenous and overexpressed human Ocrl localizes inside and at the base of the primary cilia. During cell cycle, Ocrl localizes with the centrioles, except during metaphase and anaphase; Ocrl is also detected at the midbody during cytokinesis. Lowe syndrome causing mutations in the inositol phosphatase domain of Ocrl result in failure of Ocrl to localize at the primary cilia. Interestingly, Lowe patient fibroblasts and Ocrl knockdown cells demonstrate shorter ciliary length. Notably, the ciliary GTPase Rab8A mediates recruitment of Ocrl to the primary cilia and as the Rab-binding domain of Ocrl interacts with Rab8A, we found that Lowe syndrome causing mutations in this domain disrupt ciliary recruitment of Ocrl.

Conclusions: : Our data suggest that Ocrl modulates cilia length and the interaction with Rab8A is crucial for its function at the primary cilium. Our data provide for the first time evidence of the involvement of ciliary pathways in the manifestation of Lowe syndrome.

Keywords: outflow: trabecular meshwork • proteins encoded by disease genes • development 
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