Advertisement

Retinal Degeneration is Accelerated when a Mutant Rhodopsin Transgene is Expressed on a Haploid or Null Rhodopsin Background

  • Jeanne Frederick
  • Nataliia Krasnoperova
  • Kirstin Hoffmann
  • Wolfgang Baehr
  • Janis Lem
  • Klaus Rüther

Abstract

The rod opsin Pro23His mutation accounts for approximately 12% of autosomal dominant retinitis pigmentosa (adRP) cases in the United States. To study mechanisms leading to photoreceptor degeneration, we investigated the effects of mutant and wild-type opsin stoichiometry on retinal morphology and function. We crossbred a trans-genic mouse line expressing the triple mutant, V20G, P23H, and P27L (GHL), with rhodopsin knockout mice. Retinal morphology of 30-day old GHL+ mice with two functional copies of the rod opsin gene (GHL+, rho+/+), one functional copy (GHL+, rho+/−) or no functional copies of the rod opsin gene (GHL+, rho−/−) was examined. Although mice of all three genotypes underwent reunal degeneration, the severity of the retinopathy correleted inversely with the number of wild-type opsin genes present. Mice with no functional wild-type opsin gene were most severely affected, while those with two functional copies were the least affected. Mice with a single functional vvild-type gene were intermediate in the degenerative phenotype. Correspondingly, changes in fundus morphology and ERG function. were most prominent in GHL+, rho−/− mice, whereas GHL+, rho−/− mice were similar to wild-type mice.

Keywords

Retinitis Pigmentosa Retinal Degeneration Outer Nuclear Layer Opsin Gene Functional Copy 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    T.P. Dryja and T. Li, 1995, Molecular genetics of retinitis pigmentosa, Hum. Mol. Genet. 4:1739–1743.PubMedGoogle Scholar
  2. 2.
    J. Lem and C.L. Makino, 1996, Phototransduction in transgenic mice, Curr. Opin. Neurobiol. 6:453–458.PubMedCrossRefGoogle Scholar
  3. 3.
    K. Gregory-Evans and S.S. Bhattacharya, 1998, Genetic blindness: current concepts in the pathogenesis of human outer retinal dystrophies, Trends Genet 14:103–108.PubMedCrossRefGoogle Scholar
  4. 4.
    M.I. Naash, J.G. Hollyfield, M.R. Al-Ubaidi, and W. Baehr, 1993, Simulation of human autosomal dominant retinitis pigmentosa in transgenic mice expressing a mutated murine opsin gene, Proc. Natl. Acad. Sci. U.S.A. 90:5499–5504.PubMedCrossRefGoogle Scholar
  5. 5.
    X.R. Liu, T.H. Wu, S. Stowe, A. Matsushita, K. Arikawa, M.I. Naash, and D.S. Williams, 1997, Defective phototransductive disk membrane morphogenesis in transgenic mice expressing opsin with a mutated N-terminal domain, J. Cell Sci. 110:2589–2597.PubMedGoogle Scholar
  6. 6.
    D.J. Roof, M. Adamian, and A. Hayes, 1994, Rhodopsin accumulation at abnormal sites in retinas of mice with a human P23H rhodopsin transgene, Invest. Ophthalmol. Vis. Sci. 35:4049–4062.PubMedGoogle Scholar
  7. 7.
    X. Liu, P. Garriga, and H.G. Khorana. 1996, Structure and function in rhodopsin: correct folding and misfolding in two point mutants in the intradiscal domain of rhodopsin identified in retinitis pigmentosa, Proc. Natl. Acad. Sci. USA. 93:4554–4559.PubMedCrossRefGoogle Scholar
  8. 8.
    M.M. Humphries, D. Rancourt, G.J. Farrar, P. Kenna, M. Hazel, R.A. Bush, P.A. Sieving, D.M. Shells, N. McNally, P. Creighton, A. Erven, A. Boros, K. Gulya, M.R. Capecchi, and P. Humphries, 1997, Retinopathy induced in mice by targeted disruption of the rhodopsin gene, Nature Genet. 15:216–219.PubMedCrossRefGoogle Scholar
  9. 9.
    J. Lem, P.D. Calvert, B. Kosaras, D.A. Cameron, M. Nicolo, C. Makino, and R.L. Sidman, 1999, Morphological, physiological and biochemical changes in rhodopsin knockout mice, Proc. Natl. Acad. Sci. U.S.A., submitted.Google Scholar
  10. 10.
    G.H. Travis, 1997, Insights from a lost visual pigment [news;comment], Nat. Genet 15:115–117.PubMedCrossRefGoogle Scholar
  11. 11.
    J.E. Olsson, J.W. Gordon, B.S. Pawlyk, D. Roof, A. Hayes, R.S. Molday, S. Mukai, G.S. Cowley, E.L. Berson, and T.P. Dryja, 1992, Transgenic mice with a rhodopsin mutation (Pro23His): A mouse model of autosomal dominant retinitis pigmentosa, Neuron 9:815–830.PubMedCrossRefGoogle Scholar
  12. 12.
    A.S. Lewin, K.A. Drenser, W.W. Hauswirth, S. Nishikawa, D. Yasumura, J.G. Flannery, and M.M. LaVail, 1998. Ribozyme rescue of photoreceptor cells in a transgenic rat model of autosomal dominant retinitis pigmentosa, Nat. Med 4:967–971.PubMedCrossRefGoogle Scholar

Copyright information

© Kluwer Academic / Plenum Publishers 1999

Authors and Affiliations

  • Jeanne Frederick
    • 1
  • Nataliia Krasnoperova
    • 2
  • Kirstin Hoffmann
    • 3
  • Wolfgang Baehr
    • 1
  • Janis Lem
    • 2
    • 4
  • Klaus Rüther
    • 3
  1. 1.Moran Eye CenterUniversity of Utah Health Science CenterSalt Lake City
  2. 2.Department of OphthalmologyNew England Medical CenterBoston
  3. 3.Charité-Virchow AugenklinikHumboldt UniversityBerlinGermany
  4. 4.Tufts University School of MedicineBoston

Personalised recommendations