Molecular Neurobiology

, Volume 28, Issue 2, pp 149–158 | Cite as

The nature of dominant mutations of rhodopsin and implications for gene therapy

Article

Abstract

Mutations in the rhodopsin gene are the most common cause of retinitis pigmentosa (RP) among human patients. The nature of the rhodopsin mutations has critical implications for the design of strategies for gene therapy. Nearly all rhodopsin mutations are dominant. Although dominance does not arise because of haploinsufficiency, it is unclear whether it is caused by gain-of-function or dominant-negative mutations. Current strategies for gene therapy have been devised to deal with toxic, gain-of-function mutations. However, analysis of results of transgenic and targeted expression of various rhodopsin genes in mice suggests that dominance may arise as a result of dominant-negative mutations. This has important consequences for gene therapy. The effects of dominant-negative mutations can be alleviated, in principle, by supplementation with additional wild-type rhodopsin. If added wild-type rhodopsin could slow retinal degeneration in human patients, as it does in mice, it would represent a valuable new strategy for gene therapy of RP caused by dominant rhodopsin mutations.

Index Entries

Retinitis pigmentosa rhodopsin mutations dominant mutants mouse expression studies gene therapy 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Weleber R.G. and Gregory-Evans K. (2001) Retinitis pigmentosa and allied disorders. In Retina (Ryan S.J., ed.), Mosby, St. Louis, MO, pp. 362–470.Google Scholar
  2. 2.
    Chong N.H.V. and Bird A.C. (1999) Management of inherited outer retinal dystrophies: present and future. Br. J. Ophthalmol. 83, 120–122.PubMedGoogle Scholar
  3. 3.
    Farrar G.J., Kenna P.F., and Humphries P. (2002) On the genetics of retinitis pigmentosa and on mutation-independent approaches to therapeutic intervention. EMBO J. 21, 857–864.PubMedCrossRefGoogle Scholar
  4. 4.
    Rattner A., Sun H., and Nathans J. (1999) Molecular genetics of human retinal disease. Annu. Rev. Genet. 33, 89–131.PubMedCrossRefGoogle Scholar
  5. 5.
    Rivolta C., Sharon D., DeAngelis M.M., and Dryja T.P. (2002) Retinitis pigmentosa and allied diseases: numerous diseases, genes, and inheritance patterns. Hum. Mol. Genet. 11, 1219–1227.PubMedCrossRefGoogle Scholar
  6. 6.
    http://www.sph.uth.tmc.edu/RetNet.Google Scholar
  7. 7.
    http://eyegene.meei.harvard.edu.Google Scholar
  8. 8.
    Hargrave P.E. and McDowell J.H. (1992) Rhodopsin and phototransduction: a model system for G protein-linked receptors. FASEB J. 6, 2323–2331.PubMedGoogle Scholar
  9. 9.
    Millington-Ward S., O’Neill B., Tuohy G., Al-Jandal N., Kiang A.-S., Kenna P.F., et al. (1997) Strategems in vitro for gene therapies directed to dominant mutations. Hum. Mol. Genet. 6, 1415–1426.PubMedCrossRefGoogle Scholar
  10. 10.
    Rosenfeld P.J., Cowley G.S., McGee T.L., Sandberg M.A., Berson E.L., and Dryja T.P. (1992) A null mutation in the rhodopsin gene causes rod photoreceptor dysfunction and autosomal recessive retinitis pigmentosa. Nat. Genet. 1, 209–213.PubMedCrossRefGoogle Scholar
  11. 11.
    Lem J., Krasnoperova N.V., Calvert P.D., Kosaras B., Cameron D.A., Nicolo M., et al. (1999) Morphological, physiological, and biochemical changes in rhodopsin knockout mice. Proc. Natl. Acad. Sci. USA 96, 736–741.PubMedCrossRefGoogle Scholar
  12. 12.
    Humphries M.M., Rancourt D., Farrar G.J., Kenna P., Hazel M., Bush R.A., et al. (1997) Retinopathy induced in mice by targeted disruption of the rhodopsin gene. Nat. Genet. 15, 216–219.PubMedCrossRefGoogle Scholar
  13. 13.
    Lewis E.B. (1978) A gene complex controlling segmentation in Drosophila. Nature 276, 565–570.PubMedCrossRefGoogle Scholar
  14. 14.
    Keen T.J., Inglehearn C.F., Lester D.H., Bashir R., Jay M., Bird A.C., et al. (1991) Autosomal dominant retinitis pigmentosa: four new mutations in rhodopsin, one of them in the retinal attachment site. Genomics 11, 199–205.PubMedCrossRefGoogle Scholar
  15. 15.
    Robinson P.R., Cohen G.B., Zhukovsky E.A., and Oprian D.D. (1992) Constitutively active mutants of rhodopsin. Neuron 9, 719–725.PubMedCrossRefGoogle Scholar
  16. 16.
    Downward J. (2003) Targeting RAS signaling pathways in cancer therapy. Nat. Rev. Cancer 3, 11–22.PubMedCrossRefGoogle Scholar
  17. 17.
    Fain G.L. and Lisman J.E. (1993) Photoreceptor degeneration in vitamin A deprivation and retinitis pigmentosa: the equivalent light hypothesis. Exp. Eye Res. 57, 335–340.PubMedCrossRefGoogle Scholar
  18. 18.
    Li T., Franson W.K., Gordon J.W., Berson E.L., and Dryja T.P. (1995) Constitutive activation of phototransduction by K296E opsin is not a cause of photoreceptor degeneration. Proc. Natl. Acad. Sci. USA 92, 3551–3555.PubMedCrossRefGoogle Scholar
  19. 19.
    Sung C.-H., Schneider B.G., Agarwal N., Pappermaster D.S., and Nathans J. (1991) Functional heterogeneity of mutant rhodopsins responsible for autosomal dominant retinitis pigmentosa. Proc. Natl. Acad. Sci. USA 88, 8840–8844.PubMedCrossRefGoogle Scholar
  20. 20.
    Illing M.E., Rajan R.S., Bence N.F., and Kopito R.R. (2002) A rhodopsin mutant linked to autosomal dominant retinitis pigmentosa is prone to aggregate and interacts with the ubiquitin proteasome system. J. Biol. Chem. 277, 34,150–34,160.CrossRefGoogle Scholar
  21. 21.
    Rajan R.S., Illing M.E., Bence N.F., and Kopito R.R. (2001) Specificity in intracellular protein aggregation and inclusion body formation. Proc. Natl. Acad. Sci. USA 98, 13,060–13,065.CrossRefGoogle Scholar
  22. 22.
    Tran P.B. and Miller R.J. (1999) Aggregates in neurodegenerative disease: crowds and power? Trends Neurosci. 5, 194–197.CrossRefGoogle Scholar
  23. 23.
    Kopito R.R. (2000) Aggresomes, inclusion bodies and protein aggregation. Trends Cell Biol. 10, 524–530.PubMedCrossRefGoogle Scholar
  24. 24.
    Herskowitz I. (1987) Functional inactivation of genes by dominant negative mutations. Nature 329, 219–222.PubMedCrossRefGoogle Scholar
  25. 25.
    Milner J. and Medcalf E.A. (1991) Cotranslation of activated mutant p53 with wild type drives the wild-type p53 protein into the mutant conformation. Cell 65, 765–774.PubMedCrossRefGoogle Scholar
  26. 26.
    Brachmann R.K., Vidal M., and Boeke J.D. (1996) Dominant-negative p53 mutations selected in yeast hit cancer hotspots. Proc. Natl. Acad. Sci. USA 93, 4091–4095.PubMedCrossRefGoogle Scholar
  27. 27.
    Fotiadis D., Liang Y., Filipek S., Saperstein D.A., Engel A., and Palczewski K. (2003) Rhodopsin dimers in native disc membranes. Nature 421, 127–128.PubMedCrossRefGoogle Scholar
  28. 28.
    Downer N.W. and Cone R.A. (1985) Transient dichroism in photoreceptor membranes indicates that stable oligomers of rhodopsin do not form during excitation. Biophys. J. 47, 277–284.PubMedCrossRefGoogle Scholar
  29. 29.
    Rios C.D., Jordan B.A., Gomes I., and Devi L.A. (2001) G-protein-coupled receptor dimerization: modulation of receptor function. Pharmacol. Ther. 92, 71–87.PubMedCrossRefGoogle Scholar
  30. 30.
    Bruijn L.I., Houseweart M.K., Kato S., Anderson K.L., Anderson S.D., Ohama E., et al. (1998) Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1. Science 281, 1851–1854.PubMedCrossRefGoogle Scholar
  31. 31.
    Sung C.-H., Makino C., Baylor D., and Nathans J. (1994) A rhodopsin gene mutation responsible for autosomal dominant retinitis pigmentosa results in a protein that is defective in localization to the photoreceptor outer segment. J. Neuro. Sci. 14, 5818–5833.Google Scholar
  32. 32.
    Olsson J.E., Gordon J.W., Pawlyk B.S., Roof D., Hayes A., Molday R.S., et al. (1992) Transgenic mice with a rhodopsin mutation (Pro23His): A mouse model of autosomal dominant retinitis pigmentosa. Neuron 9, 815–830.PubMedCrossRefGoogle Scholar
  33. 33.
    Frederick J.M., Krasnoperova N.V., Hoffmann K., Church-Kopish J., Ruther K., Howes K., et al. (2001) Mutant rhodopsin transgene expression on a null background. Investig. Ophthalmol. Vis. Sci. 42, 826–833.Google Scholar
  34. 34.
    Lewin A.S., Drenser K.A., Hauswirth W.W., Nishikawa S., Yasumura D., Flannery J.G., et al. (1998) Ribozyme rescue of photoreceptor cells in a transgenic rat model of autosomal dominant retinitis pigmentosa. Nat. Med. 4, 967–971.PubMedCrossRefGoogle Scholar
  35. 35.
    LaVail M.M., Yasumura D., Matthes M.T., Drenser K.A., Flannery J.G., Lewin A.S., et al. (2000) Ribozyme rescue of photoreceptor cells in P23H transgenic rats: long-term survival and late-stage therapy. Proc. Natl. Acad. Sci. USA 97, 11,488–11,493.CrossRefGoogle Scholar
  36. 36.
    Intody Z., Perkins B.D., Wilson J.H., and Wensel T.G. (2000) Blocking transcription of the human rhodopsin gene by triplex-mediated DNA photocrosslinking. Nucleic Acids Res. 28, 4283–4290.PubMedCrossRefGoogle Scholar
  37. 37.
    Roorda A. and Williams D.R. (1999) The arrangement of the three cone classes in the living human eye. Nature 397, 520–522.PubMedCrossRefGoogle Scholar
  38. 38.
    Liang J., Williams D.R., and Miller D.T. (1997) Supernormal vision and high-resolution imaging through adaptive optics. J. Opt. Soc. Am. 14, 2884–2892.Google Scholar
  39. 39.
    McNally N., Kenna P., Humphries M.M., Hobson A.H., Khan N.W., Bush R.A., et al. (1999) Structural and functional rescue of murine rod photoreceptors by human rhodopsin transgene. Hum. Mol. Genet. 8, 1309–1312.PubMedCrossRefGoogle Scholar
  40. 40.
    Li T., Snyder W.K., Olsson J.E., and Dryja T.P (1996) Transgenic mice carrying the dominant rhodopsin mutation P347S: Evidence for defective vectorial transport of rhodopsin to the outer segments. Proc. Natl. Acad. Sci. USA 93, 14,176–14,181.Google Scholar
  41. 41.
    Li T., Sandberg M.A., Pawlyk B.S., Rosner B., Hayes K.C., Dryja T.P., et al. (1998) Effect of vitamin A supplementation on rhodopsin mutants threonine-17 to methionine and proline-347 to serine in transgenic mice and in cell cultures. Proc. Natl. Acad. Sci. USA 95, 11,933–11,938.Google Scholar
  42. 42.
    Naash M.I., Hollyfield J.G., Al-Ubaidi M.R., and Baehr W. (1993) Simulation of human autosomal dominant retinitis pigmentosa in transgenic mice expressing a mutated murine opsin gene. Proc. Natl. Acad. Sci. USA 90, 5499–5503.PubMedCrossRefGoogle Scholar
  43. 43.
    Goto Y., Peachey N.S., Ripps H., and Naash M.I. (1995) Functional abnormalities in transgenic mice expressing a mutant rhodopsin gene. Investig. Ophthalmol. Vis. Sci. 36, 62–71.Google Scholar
  44. 44.
    Tan E., Wang Q., Quiambao A.B., Xu X., Qtaishat N.M., Peachey N.S., et al. (2001) The relationship between opsin overexpression and photoreceptor degeneration. Investig. Ophthalmol. Vis. Sci. 42, 589–600.Google Scholar
  45. 45.
    Chen J., Makino C.L., Peachey N.S., Baylor D.A., and Simon M.I. (1995) Mechanisms of rhodopsin inactivation in vivo as revealed by a COOH-terminal truncation mutant. Science 267, 374–377.PubMedCrossRefGoogle Scholar
  46. 46.
    Soukharev S., Miller J.L., and Sauer B. (1999) Segmental genomic replacement in embryonic stem cells by double lox targeting. Nucleic Acids Res. 27, e21.Google Scholar

Copyright information

© Humana Press Inc 2003

Authors and Affiliations

  1. 1.Verna and Marrs McLean Department of Biochemistry and Molecular BiologyBaylor College of MedicineHouston

Personalised recommendations