A gene (RPGR) with homology to the RCC1 guanine nucleotide exchange factor is mutated in X–linked retinitis pigmentosa (RP3)

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Abstract

X-linked retinitis pigmentosa (xIRP) is a severe progressive retinal degeneration which affects about 1 in 25,000 of the population. The most common form of xIRR RP3, has been localised to the interval between CYBB and OTC in Xp21.1 by linkage analysis and deletion mapping. Identification of microdeletions within this region has now led to the positional cloning of a gene, RPGR, that spans 60 kb of genomic DMA and is ubiquitously expressed. The predicted 90 kD protein contains in its N-terminal half a tandem repeat structure highly similar to RCC1 (regulator of chromosome condensation), suggesting an interaction with a small GTPase. The C-terminal half contains a domain, rich in acidic residues, and ends in a potential isoprenylation anchorage site. The two intragenic deletions, two nonsense and three missense mutations within conserved domains provide evidence that RPGR (retinitis pigmentosa GTPase regulator) is the RP3 gene.

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References

  1. 1

    Heckenlively, J.R. Retinitis Pigmentosa 1–269 (Lippincott Company, Philadelphia, 1988).

  2. 2

    Dryja, T.P. & Li, T. Molecular genetics of retinitis pigmentosa. Hum. Molec. Genet. 4, 1739–1743 (1995).

  3. 3

    Bircl, A.C. X-linked retinitis pigmentosa. Br. J. Ophthalmol. 59, 177–199 (1975).

  4. 4

    Fishman, G.A., Farber, M.D. & Deriacki, D.J. X-linked retinitis pigmentosa: profile of clinical findings. Arch. Ophthalmol. 106, 369–375 (1988).

  5. 5

    Jay, M. On the heredity of retinitis pigmentosa. Br. J. Ophthalmol. 66, 405–416 (1982).

  6. 6

    fishmen, G.A., Retinitis pigmentosa.Genetic percentages. Arch. Ophthalmol. 96, 822–326 (1978).

  7. 7

    Well, D. et al. Defective myosin VIIA gene responsible for Usher Syndrome type IB. Nature 374, 60–61 (1995).

  8. 8

    Narcisi, T.M.E. et al. Mutations of the microsomal triglyceride-transfer-protein gene in abetalipoproteinemia. Am. J. Hum. Genet. 57, 1298–1310 (1995).

  9. 9

    Holt, I.J., Handing, A.E., Petty, R.K. & Mogan-Hughes, J.A., A new mitochondria) disease associated with mitochondrial DNA heteroplasmy. Am. J. Hum. Genet. 46, 428–433 (1990).

  10. 10

    Bhattacharya, S.S. et al. Close genetic linkage between X-linked retinitis pigmentosa and a restriction fragment length polymorphism identified by recombinant DNA probe L1.28. Nature 309, 253–255 (1984).

  11. 11

    Ott, J. et al. Localizing multiple X chromosome-linked retinitis pigmentosa loci using multilocus homogeneity tests. Proc. Natl. Acad. Sd. USA. 87, 701–704 (1990).

  12. 12

    McGuire, R.E. et al. X-linked dominant cone-rod degeneration: linkage mapping of a new locus for retinitis pigmentosa (RP15) to Xp22.13-p22.11. Am. J. Hum. Genet. 57, 87–94 (1995).

  13. 13

    Musarella, M.A. et al. Multipoint linkage analysis and heterogeneity testing in 20 X-linked retinitis pigmentosa families. Genomics 8, 286–296 (1990).

  14. 14

    Chen, J.D. et al. Linkage heterogeneity between X-linked retinitis pigmentosa andamapof 10RFLP loci. Am. J. Hum. Genet. 46, 401–411 (1989).

  15. 15

    league, P.W. et al. Heterogeneity analysis in 40 X-linked retinitis pigmentosa families. Am. J. Hum. Genet. 55, 105–111 (1994).

  16. 16

    Bargen, A.A.B. et al. Multipoint linkage analysis and homogeneity tests in 15 Dutch X-linked retinitis pigmentosa families. Ophthal. Genet. 16, 63–70 (1995).

  17. 17

    Roux, A.-F. et al.ldentrficationofagenefromXp21 with similarity to the tctex-1 gene of the murine t complex. Hum. Molec. Genet. 3, 257–263 (1994).

  18. 18

    Aldred, M.A., Jay, M. & Wright, A.F. X-linked retinitis pigmentosa. in Wright A.F., Jay B. (eds) The Molecular Genetics of Inherited Eye Disorders, Harwood Academic Publishers, Switzerland, 259–276 (1994).

  19. 19

    Francke, U. et al. Minor Xp21 chromosome deletion in a male associated with expression of Duchenne muscular dystrophy, chronic granulomatous disease, retinitis pigmentosa and McLeod syndrome. Am. J. Hum. Genet. 37, 250–267 (1985).

  20. 20

    De Saint-Basile, G. et al. Xp21 DNA microdeletion in a patient with chronic granulomatous disease, retinitis pigmentosa, and McLeod phenotype. Hum. Genet. 80, 85–89 (1988).

  21. 21

    Meindl, A. et al. A gene (SRPX) encoding a sushi-repeat-containing protein is deleted in patients with X-linked retinitis pigmentosa. Hum. Molec. Genet. 4, 2339–2346 (1995).

  22. 22

    Dry, K.L. et al. Identification of a novel gene, ETX1, from Xp21.1, a candidate gene for X-linked retinitis pigmentosa (RP3). Hum. Molec. Genet. 4, 2347–2353 (1995).

  23. 23

    Uberbacher, E.C. & Mural, R.J. Locating protein-coding regions in human DNA sequences by a multiple sensor-neural network approach. Proc. Natl. Acad. Sci. USA. 88, 11261–11265 (1991).

  24. 24

    Murakawa, K., Matsubara, K., Fukushima, A., Yoshii, J. & Okubo, K. Chromosomal assignments of 3′-directed partial cDNA sequences representing novel genes expressed in granulocytoid cells. Genomics 23, 379–389 (1994).

  25. 25

    Kozak, M. Structural features in eukaryotic mRNAs that modulate the initiation of translation. J. Biol. Chem. 266, 19867–19870 (1991).

  26. 26

    Wennborg, A., Sohlberg, B., Angerer, D., Klein, G. & von Gabain, A. A human RNase E-like activity that cleaves RNA sequences involved in mRNA stability control. Proc. Natl. Acad. Sd. USA. 92, 7322–7326 (1995).

  27. 27

    Dasso, M. RCC1 in the cell cycle: the regulator of chromosome condensation takes on new roles. Trends Biochem. Sci. 18, 96–101 (1993).

  28. 28

    Ohtsubo, M., et al. Isolation and charcterization of the active cDNA of the human cell cycle gene (RCC1) involved in the regulation of onset of chromosome condensation. Genes Devel. 1, 585–593 (1987).

  29. 29

    Nomura, N. et al. Prediction of the coding sequences of unidentified genes. I. The coding sequences of 40 new genes (KIM0001-KIAA0040) deduced by analysis of randomly sampled cDNA clones from human immature myeloid celllineKG-1 (supplement)DNA Res. 1, 47–56 (1994).

  30. 30

    Nishitani, H., Kobayashi, H., Ohtsubo, M. & Nishimoto, T. Cloning of Xenopus RCC1 cDNA, a homolog of the human RCC1 gene: complementation of tsBN2 mutation and identification of the product. J. Biochem. 107, 228–235.

  31. 31

    Clark, K.L. & Sprague, G.F. Yeast pheromone response pathway: characterization of a suppressor that restores mating to receptorless mutants. Molec. Cell. Biol. 9, 2682–2694 (1989).

  32. 32

    Moore, M.S. Protein translocation: nuclear export - out of the dark. Curr. Bid. 6, 137–140 (1996).

  33. 33

    Gorbatenya, A.E., Koonin, E.V., Donchenko, A.P. & Blinov, V.M. Two related superfamilies of putative helicases involved in replication, recombination, repair and expression of DNA and RNA genomes. Nucl. Acids Res. 17, 4713–4730 (1989).

  34. 34

    Kemp, B.E. & Pearson, R.B. Protein kinase recognition sequence motifs. Trends Biochem. Sci. 15, 342–346 (1990).

  35. 35

    Brown, M.S., Goktetein, L., 366, 14–15 (1993).

  36. 36

    Chou, R.Y., & Fasman, G.D . Prediction of the secondary structure of proteins from their amino acid sequence. Adv. Enzymol. 47, 45–147 (1978).

  37. 37

    Furuno, N. et al. Complete nucteotide sequence of the human RCC1 gene involved in coupling between DNA replication and mitosis. Genomics 11, 459–461 (1991).

  38. 38

    Bassi, M.T. et al. Cloning of the gene for ocular albinism type 1 from the distal short arm of the X chromsome. Nature Genet. 10, 13–19 (1995).

  39. 39

    Muscatelli, F. et al. Mutations in the DAX-1 gene give rise to both X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism. Nature 372, 672–676 (1994).

  40. 40

    Ketteriing, R.R., Liao, D. & Sommer, S.S. Are some apparently simple deletions actually two concerted deletions that result from interacting RY(i) hairpin loops?. Am. J. Hum. Genet. 56, 343–346 (1995).

  41. 41

    Bischoff, F.R. & Ponstingl, H. Catalysis of guanine nucteotide exchange on Ran by the mitotic regulator RCC1. Nature 354, 80–82 (1991).

  42. 42

    Rush, M., Drivas, G. & D'Eustachio, P. The small nuclear GTPase Ran: how much does it run?. BbEssays. 18, 103–112 (1996).

  43. 43

    Scheffzek, K., Ktebe, C., Fritz-Wolf, K., Kabsch, W. & Wittinghofer, A. Crystal structure of the nuclear Ras-related protein Ran in its GDP-bound form. Nature 374, 378–381 (1995).

  44. 44

    Cheng, Y., Dahlberg, J.E. & Lund, E. Diverse effects of the guanine nucleotide exchangefactorRCCI on RNA transport. Science. 267, 1807–1810 (1995).

  45. 45

    Klebe, C., Bischoff, F.R., Ponstingl, H. & Wittinghofer, A. Interaction of the nuclear GTP-binding protein Ran with its regulatory proteins RCC1 and RanGAPI. Biochem. 34, 639–647 (1995).

  46. 46

    Beddow, A.L., Richards, S.A., Orem, N.R. & Macara, I.G., GTPase-binding domain: identification by expression cloning and charcterization of a conserved sequence motif. Proc. Natl. Acad. Sci. USA. 92, 3328–3332 (1995).

  47. 47

    Saitoh, H. & Dasso, M. The RCC1 protein interacts with Ran, RanBPI, hsc70, and a 340-kDa protein in Xenopus extracts. J. Biol. Chem. 270, 10658–10663 (1995).

  48. 48

    Ren, M. et al. Separate domains of the Ran GTPase interact with different factors to regulate nuclear protein import and RNA processing. Motec. Cell. Btol. 15, 2117–2124 (1995).

  49. 49

    Coutavas, E.E. et al. Tissue-specific expression of Ran isoforms in the mouse. Mamm. Genome. 5, 623–628 (1994).

  50. 50

    Biochemistry of the Eye(Ed. Berman, E.R.) (Plenum, New York, 1991).

  51. 51

    Seabra, M.C., Brown, M.S. & Goldstein, J.L. Retinal degeneration in choroideremia: deficiency of Rab geranylgeranyl transferase. Science. 259, 377–381 (1993).

  52. 52

    Nizetic, D. et al. Construction, arraying and high-density screening of large insert libraries of human chromosomes X and 21: their potential use as reference libraries. Proc. Natl. Acad. Sd. USA. 88, 3233–3237 (1991).

  53. 53

    Pearson, W.R. & Lipman, D.J. Improved tools for biological sequence comparison. Proc. Natl. Acad. Sd. USA. 85, 2444–2448 (1988).

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Meindl, A., Dry, K., Herrmann, K. et al. A gene (RPGR) with homology to the RCC1 guanine nucleotide exchange factor is mutated in X–linked retinitis pigmentosa (RP3). Nat Genet 13, 35–42 (1996) doi:10.1038/ng0596-35

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