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Human Molecular Genetics Advance Access published online on March 16, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi129
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received November 14, 2004
Revised February 18, 2005
Accepted March 10, 2005

Article

RPGR ORF15 isoform co-localises with RPGRIP1 at centrioles and basal bodies and interacts with nucleophosmin

Shu X 1, Fry AM 2, Tulloch B 1, Manson FDC 3, Crabb JW 4, Khanna H 5, Faragher AJ 2, Lennon A 1, He S 5, Trojan P 6, Giessl A 6, Wolfrum U 6, Vervoort R 1, Swaroop A 5, and Wright AF 1*

1 MRC Human Genetics Unit, Western General Hospital, Edinburgh, EH4 2XU, UK
2 Department of Biochemistry, University of Leicester, Leicester LE1 7RH, UK
3 MRC Human Genetics Unit, Western General Hospital, Edinburgh, EH4 2XU, UK; Current address: Centre for Molecular Medicine, The University of Manchester, Oxford Road, Manchester M13 9PT, UK
4 Cole Eye Institute and Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
5 Departments of Ophthalmology and Human Genetics, W.K. Kellogg Eye Center, University of Michigan, Ann Arbor, MI, USA
6 Institute for Zoology, Johannes Gutenberg-University, Mainz, Germany.

* To whom correspondence should be addressed.
Wright AF, E-mail: alan.wright{at}hgu.mrc.ac.uk


  Abstract

The ORF15 isoform of RPGR (RPGRORF15) and its interacting protein, RPGRIP1, are mutated in a variety of retinal dystrophies but their functions are poorly understood. Here, we show that in cultured mammalian cells both RPGRORF15 and RPGRIP1 localise to centrioles. These localisations are resistant to the microtubule destabilising drug nocodazole and persist throughout the cell cycle. RPGR and RPGRIP1 also co-localise at basal bodies in cells with primary cilia. The carboxyl terminal (C2) domain of RPGRORF15 (ORF15C2) is highly conserved across 18 mammalian species, suggesting that it is a functionally important domain. Using MALDI-ToF mass spectrometry, we show that this domain interacts with a 40 kD shuttling protein nucleophosmin (NPM). The RPGRORF15-NPM interaction was confirmed by (i) yeast two-hybrid analyses; (ii) binding of both recombinant and native HeLa cell NPM to RPGRORF15 fusion proteins in vitro; (iii) co-immunoprecipitation of native NPM, RPGRORF15 and RPGRIP1 from bovine retinal extracts, and of native HeLa cell NPM and transfected RPGRORF15 from cultured cells; and (iv) co-localisation of NPM and RPGRORF15 at metaphase centrosomes in cultured cells. NPM is a multifunctional protein chaperone that shuttles between nucleoli and the cytoplasm and has been associated with licensing of centrosomal division. RPGR and RPGRIP1 join a growing number of centrosomal proteins involved in human disease.


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