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Functional analyses of RP2, a novel retinal degeneration protein

Grayson, Celene; (2003) Functional analyses of RP2, a novel retinal degeneration protein. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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X-linked retinitis pigmentosa (XLRP) is a heterogeneous disease causing a severe form of retinal degeneration. RP2 is a novel gene that accounts for up to 15% of XLRP and encodes a ubiquitously expressed protein that shares homology with the tubulin-specific chaperone, cofactor C. The localisation of RP2 protein was investigated in cells and in tissues and was found to localise to the plasma membrane in all human cell lines tested, and this was mediated by dual N-terminal acylation. The plasma membrane localisation of RP2 was also defined in cells throughout the human retina, including both rod and cone photoreceptors, with no observed enrichment of RP2 staining in any photoreceptor organelle. The retinal localisation of cofactor C and an identified RP2 interacting protein, Arl3, were also investigated and compared. Unlike RP2, cofactor C and Arl3 localised predominantly to the photoreceptor connecting cilium in rod and cone photoreceptors. Cofactor C was cytoplasmic in distribution, whereas Arl3 localised to other microtubule structures within all cells. Arl3 behaved as a microtubule-associated protein (MAP): it co-localised with microtubules in cells and co-purified with microtubules. RP2 was also shown to associate with microtubules and further evidence supporting a cytoskeletal association for RP2 was obtained using bioinformatic analysis. Collectively, these data support the hypothesis that RP2 may function to link the membrane to the cytoskeleton in photoreceptor cells in the retina. Lymphoblastoid cells from XLRP patients, with defined protein truncating mutations in RP2 were found not to express full length or truncated RP2 protein. Furthermore, the expression levels of cofactor C and Arl3 were not affected by the absence of RP2 in these cells. A potential drug-mediated therapy to restore RP2 function in these patients with pathogenic nonsense mutations was evaluated. The data presented in this thesis suggest that mutations in RP2 may cause retinitis pigmentosa by leading to the degradation of the RP2 protein, by interfering with the normal targeting of the protein to the membrane, or disrupting the functional relationship with tubulin and other partner proteins.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Functional analyses of RP2, a novel retinal degeneration protein
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences; Retinitis pigmentosa
URI: https://discovery.ucl.ac.uk/id/eprint/10100824
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