Human Molecular Genetics, 2000, Vol. 9, No. 13 1919-1926
© 2000 Oxford University Press
Mutations in the N-terminus of the X-linked retinitis pigmentosa protein RP2 interfere with the normal targeting of the protein to the plasma membrane
Department of Pathology and 1Department of Molecular Genetics, Institute of Ophthalmology, University College London, 11–43 Bath Street, London EC1V 9EL, UK and 2Institute of Cancer Research, Chester Beatty Laboratories, London, UK
The X-linked retinitis pigmentosa (XLRP) gene, RP2, codes for a novel 350 amino acid protein of unknown function. We have identified putative sites for N-terminal acyl modification by myristoylation and palmitoylation in the RP2 protein. The RP2 protein is expressed ubiquitously in human tissues at relatively low levels (0.01% of total protein) and has a predominantly plasma membrane localization in cultured cells, as would be expected if the protein was subject to dual N-terminal acylation. Furthermore, mutagenesis of residues potentially required for N-terminal acylation prevents targeting of RP2 to the plasma membrane and the N-terminal 15 amino acids of the protein appear to be sufficient for this targeting. Our data suggest that the protein is dually acylated and that the palmitoyl moiety is responsible for targeting of the myristoylated protein from intracellular membranes to the plasma membrane. The effect of two mutations, which have been reported as causes of XLRP, R118H and 
S6, were investigated. The R118H mutation does not affect the normal plasma membrane localization of RP2; in contrast, the S6 mutation interferes with the targeting of the protein to the plasma membrane. Therefore, the S6 mutation may cause XLRP because it prevents normal amounts of RP2 reaching the correct cellular locale, whereas the R118H mutation is in a region of the protein that is vital for another aspect of RP2 function in the retina.
+ To whom correspondence should be addressed. Tel: +44 20 7608 6944; Fax: +44 20 7608 6862; Email: michael.cheetham@ucl.ac.uk
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  H. Prokisch, M. Hartig, R. Hellinger, T. Meitinger, and T. Rosenberg A Population-Based Epidemiological and Genetic Study of X-Linked Retinitis Pigmentosa Invest. Ophthalmol. Vis. Sci., September 1, 2007; 48(9): 4012 - 4018. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Garcia-Hoyos, B. Garcia-Sandoval, D. Cantalapiedra, R. Riveiro, I. Lorda-Sanchez, M. J. Trujillo-Tiebas, M. Rodriguez de Alba, J. M. Millan, M. Baiget, C. Ramos, et al. Mutational Screening of the RP2 and RPGR Genes in Spanish Families with X-Linked Retinitis Pigmentosa. Invest. Ophthalmol. Vis. Sci., September 1, 2006; 47(9): 3777 - 3782. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. J. Barnes, J. Richards, M. Mancl, S. Hanash, L. Beretta, and P. M. Pitha Global and Distinct Targets of IRF-5 and IRF-7 during Innate Response to Viral Infection J. Biol. Chem., October 22, 2004; 279(43): 45194 - 45207. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S S Dandekar, N D Ebenezer, C Grayson, J P Chapple, C A Egan, G E Holder, S A Jenkins, F W Fitzke, M E Cheetham, A R Webster, et al. An atypical phenotype of macular and peripapillary retinal atrophy caused by a mutation in the RP2 gene Br J Ophthalmol, April 1, 2004; 88(4): 528 - 532. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I Zito, S M Downes, R J Patel, M E Cheetham, N D Ebenezer, S A Jenkins, S S Bhattacharya, A R Webster, G E Holder, A C Bird, et al. RPGR mutation associated with retinitis pigmentosa, impaired hearing, and sinorespiratory infections J. Med. Genet., August 1, 2003; 40(8): 609 - 615. [Full Text]
|
|
|
|
|
|
J. P. Chapple and M. E. Cheetham The Chaperone Environment at the Cytoplasmic Face of the Endoplasmic Reticulum Can Modulate Rhodopsin Processing and Inclusion Formation J. Biol. Chem., May 23, 2003; 278(21): 19087 - 19094. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Bader, O. Brandau, H. Achatz, E. Apfelstedt-Sylla, M. Hergersberg, B. Lorenz, B. Wissinger, B. Wittwer, G. Rudolph, A. Meindl, et al. X-linked Retinitis Pigmentosa: RPGR Mutations in Most Families with Definite X Linkage and Clustering of Mutations in a Short Sequence Stretch of Exon ORF15 Invest. Ophthalmol. Vis. Sci., April 1, 2003; 44(4): 1458 - 1463. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Grayson, F. Bartolini, J. P. Chapple, K. R. Willison, A. Bhamidipati, S. A. Lewis, P. J. Luthert, A. J. Hardcastle, N. J. Cowan, and M. E. Cheetham Localization in the human retina of the X-linked retinitis pigmentosa protein RP2, its homologue cofactor C and the RP2 interacting protein Arl3 Hum. Mol. Genet., November 15, 2002; 11(24): 3065 - 3074. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. S. Saliba, P. M. G. Munro, P. J. Luthert, and M. E. Cheetham The cellular fate of mutant rhodopsin: quality control, degradation and aggresome formation J. Cell Sci., July 15, 2002; 115(14): 2907 - 2918. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P. Chapple, A. J. Hardcastle, C. Grayson, K. R. Willison, and M. E. Cheetham Delineation of the Plasma Membrane Targeting Domain of the X-Linked Retinitis Pigmentosa Protein RP2 Invest. Ophthalmol. Vis. Sci., June 1, 2002; 43(6): 2015 - 2020. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Bartolini, A. Bhamidipati, S. Thomas, U. Schwahn, S. A. Lewis, and N. J. Cowan Functional Overlap between Retinitis Pigmentosa 2 Protein and the Tubulin-specific Chaperone Cofactor C J. Biol. Chem., April 19, 2002; 277(17): 14629 - 14634. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C Grayson, J P Chapple, K R Willison, A R Webster, A J Hardcastle, and M E Cheetham In vitro analysis of aminoglycoside therapy for the Arg120stop nonsense mutation in RP2 patients J. Med. Genet., January 1, 2002; 39(1): 62 - 67. [Full Text] [PDF]
|
|
|
|
|
|
U. Schwahn, N. Paland, S. Techritz, S. Lenzner, and W. Berger Mutations in the X-linked RP2 gene cause intracellular misrouting and loss of the protein Hum. Mol. Genet., May 1, 2001; 10(11): 1177 - 1183. [Abstract] [Full Text] [PDF]
|
|