May 2008
Volume 49, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2008
Missense Mutations in RPGRIP1L Are Associated With Early-Onset Retinal Degeneration and Alter Its Interaction With RPGR and Selected NPHP and BBS Ciliary Proteins
Author Affiliations & Notes
  • H. Khanna
    Ophthalmology, Univ of Michigan-Kellogg Eye Ctr, Ann Arbor, Michigan
  • A. Estrada
    Ophthalmology, Univ of Michigan-Kellogg Eye Ctr, Ann Arbor, Michigan
  • C. M-Zamalloa
    Ophthalmology, Univ of Michigan-Kellogg Eye Ctr, Ann Arbor, Michigan
  • I. Lopez
    Ocular Genetics Laboratory, McGill University Health Centre, Montreal, Quebec, Canada
  • N. Waseem
    Ophthalmology, Institute of Ophthalmology, University College London, United Kingdom
  • A. I. den Hollander
    Human Genetics, Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands
  • M. I. Othman
    Ophthalmology, Univ of Michigan-Kellogg Eye Ctr, Ann Arbor, Michigan
  • S. S. Bhattacharya
    Ophthalmology, Institute of Ophthalmology, University College London, United Kingdom
  • R. K. Koenekoop
    Ocular Genetics Laboratory, McGill University Health Centre, Montreal, Quebec, Canada
  • A. Swaroop
    Ophthalmology, Univ of Michigan-Kellogg Eye Ctr, Ann Arbor, Michigan
  • Footnotes
    Commercial Relationships  H. Khanna, None; A. Estrada, None; C. M-Zamalloa, None; I. Lopez, None; N. Waseem, None; A.I. den Hollander, None; M.I. Othman, None; S.S. Bhattacharya, None; R.K. Koenekoop, None; A. Swaroop, None.
  • Footnotes
    Support  NIH Grant EY007961, FFB USA, FFB Canada, Fonds de la Recherche en Sante'e du Quebec, European Union Grant, Research to Prevent Blindness
Investigative Ophthalmology & Visual Science May 2008, Vol.49, 3286. doi:https://doi.org/
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      H. Khanna, A. Estrada, C. M-Zamalloa, I. Lopez, N. Waseem, A. I. den Hollander, M. I. Othman, S. S. Bhattacharya, R. K. Koenekoop, A. Swaroop; Missense Mutations in RPGRIP1L Are Associated With Early-Onset Retinal Degeneration and Alter Its Interaction With RPGR and Selected NPHP and BBS Ciliary Proteins. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3286. doi: https://doi.org/.

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

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Abstract

Purpose: : Mutations in the cilia-centrosomal protein RPGR and its interacting proteins are a major cause of retinal degeneration and syndromic ciliopathies. In this study, we describe mutations and dysfunction of a RPGR-interacting protein, RPGRIP1L (mutated in Joubert Syndrome (JBTS) and Meckel-Gruber Syndrome) in Leber congenital amaurosis and RP.

Methods: : RPGR-interacting proteins were identified by yeast two-hybrid screening of a retina prey cDNA library using RPGR1-ORF15 bait. This interaction was validated by co-transfection and co-IP experiments. Over 200 LCA and RP patients were screened by dHPLC and direct sequencing of the RPGRIP1L gene.

Results: : We identified RPGRIP1L as an RPGR-interacting protein in ciliated cells as well as in bovine retinal extracts. In addition to Nephroretinin (NPHP4), RPGRIP1L interacts with RPGRIP1 and with selected Bardet-Biedl Syndrome and Nephronophthisis (NPHP) proteins. We found 11 heterozygous missense variants in RPGRIP1L in 13 LCA patients; of these, 8 also harbored significant mutations in other LCA genes: i.e LCA5 (Q279X), RPGRIP1 (R890X), CRB1 (C948Y) and RPGR (I1148V). We identified the JBTS mutation T677I in RPGRIP1L in LCA patients and excluded it from 250 normal controls; however, this mutation did not co-segregate in the pedigree. Importantly, our results show that disease-associated RPGRIP1L variants may differentially alter its interactions with RPGR, NPHP, and BBS proteins.

Conclusions: : Absence of co-segregation and a second mutation precludes RPGRIP1L as a cause of LCA. However, our data suggest that the identified missense RPGRIP1L variants may play a role in the pathogenesis of LCA, by probably acting as a modifier. We propose that disruption of the RPGR-RPGRIP1L interactome is a likely cause of associated RP and related ciliopathies.

Keywords: photoreceptors • retinal degenerations: cell biology • proteins encoded by disease genes 
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