The RPE65-Deficient Mouse as a Model for RPE65-Associated Leber’s Congenital Amaurosis and Related Disorders

  • T. Michael Redmond


The retinal pigment epithelium (RPE)-specific protein RPE65 has been speculated to play a role in the vitamin A metabolism of the outer retina. Recently, mutations in the human RPE65 gene have been associated with Leber’s congenital amaurosis, a disorder characterized by blindness at birth, and autosomal recessive childhood-onset severe retinal dystrophies. We have developed an RPE65-deficient mouse and have described its phenotype. The RPE65-deficient mouse phenotype parallels that of the human disorders. This phenotype can be explained by a disruption of the RPE visual cycle causing a lack of 11-cis-retinal chromophore. Consequently, it is feasible to use this mouse as a model to test possible therapies for the human diseases.


Retinal Pigment Epithelium Retinal Dystrophy Retinyl Ester Visual Cycle Retinal Pigment Epithe 


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  1. 1.
    J.G. Cunha-Vaz, 1976, The blood-retinal barriers, Doc. Ophthalmol. 41:287–327.PubMedCrossRefGoogle Scholar
  2. 2.
    R. W. Young, and D. Bok, 1969, Participation of the retinal pigment epithelium in the rod outer segment renewal process, J. Cell Biol. 42:392–403.PubMedCrossRefGoogle Scholar
  3. 3.
    R.W. Young, and D. Bok, 1970, Autoradiographic studies on the metabolism of the retinal pigment epithelium, Invest. Ophthalmol. 9:524–536.PubMedGoogle Scholar
  4. 4.
    J.C. Saari, 1994, Retinoids in photosensitive systems, in: The Retinoids: Biology, Chemistry, and Medicine, 2nd Ed. (Eds: Sporn, M.B., Roberts, A.B., and Goodman, D.S.) 351–385, Raven, New York.Google Scholar
  5. 5.
    G. Wald, 1968, Molecular basis of visual excitation, Science 162:230–239.PubMedCrossRefGoogle Scholar
  6. 6.
    R.J. Barry, F.J. Canada, and R.R. Rando, 1989, Solubilization and partial purification of retinyl ester synthetase and retinoid isomerase from bovine ocular pigment epithelium, J. Biol. Chem. 264:9231–9238.PubMedGoogle Scholar
  7. 7.
    G. Travis, 1997, Insights from a lost visual pigment, Nature Genet. 15:115–117.PubMedCrossRefGoogle Scholar
  8. 8.
    Y.L. Lai, B. Wiggert, Y.P. Liu, and G.J. Chader, 1982, Interphotoreceptor retinol-binding protein: Possible transport vehicles between compartments of the retina, Nature 298:848–849.PubMedCrossRefGoogle Scholar
  9. 9.
    K. Palczewski, S. Jager, J. Buczylko, R.K. Crouch, D.L. Bredberg, K.P. Hofmann, M.A. Asson-Batres, and J.C. Saari, 1994, Rod outer segment retinol dehydrogenase: substrate specificity and role in phototransduction, Biochemistry 33:13741–13750.PubMedCrossRefGoogle Scholar
  10. 10.
    J.C. Saari, and D.L. Bredberg, 1989, Lecithin: retinol acyl transferase in retinal pigment epithelial microsomes, J. Biol. Chem. 264:8636–8640.PubMedGoogle Scholar
  11. 11.
    A. Simon, U. Hellman, C. Wernstedt, and U. Eriksson, 1995, The retinal pigment epithelial-specific 11-cis retinol dehydrogenase belongs to the family of short chain dehydrogenases, J. Biol. Chem. 270:1107–1112.PubMedCrossRefGoogle Scholar
  12. 12.
    J.C. Saari, D.L. Bredberg, and N. Noy, 1994, Control of substrate flow at a branch in the visual cycle, Biochemistry 33:3106–3112.PubMedCrossRefGoogle Scholar
  13. 13.
    P.S. Bernstein, W.C. Law, and R.R. Rando, 1987, Biochemical characterization of the retinoid isomerase system of the eye, J. Biol. Chem. 262:16848–16857.PubMedGoogle Scholar
  14. 14.
    P.S. Deigner, W.C. Law, F.C. Cañada, and R.R. Rando, 1989, Membranes as the energy source in the endergonic transformation of vitamin A to 11-cis-retinol, Science 244:968–971.PubMedCrossRefGoogle Scholar
  15. 15.
    A. Winston, and R.R. Rando, 1998, Regulation of isomerohydrolase in the visual cycle, Biochemistry 37:2044–2050.PubMedCrossRefGoogle Scholar
  16. 16.
    M.A. Maw, B. Kennedy, A. Knight, R. Bridges, K.E. Roth, E.J. Mani, J.K. Mukkadan, D. Nancarrow, J.W. Crabb, and M.J. Denton, 1997, Mutation of the gene encoding cellular retinaldehyde-binding protein in autosomal recessive retinitis pigmentosa, Nature Genet. 17:198–200.PubMedCrossRefGoogle Scholar
  17. 17.
    G.J. Jones, R.K. Crouch, B. Wiggert, M.C. Cornwall, and Chader, G.J., 1989, Retinoid requirements for recovery of sensitivity after visual-pigment bleaching in isolated photoreceptors, Proc. Natl. Acad. Sci. USA 86:9606–9610.PubMedCrossRefGoogle Scholar
  18. 18.
    G.I. Liou, Y. Fei, N.S. Peachey, S. Matragoon, S. Wei, W.S. Blaner, Y. Wang, C. Liu. M.E. Gottesman, H. Ripps, 1998. Early onset photoreceptor abnormalities induced by targeted disruption of the interphotoreceptor retinoid-binding protein gene, J. Neurosci. 18:4511–4520.PubMedGoogle Scholar
  19. 19.
    A.F. Wright, 1997, A searchlight through the fog, Nature Genet. 17:132–134.PubMedCrossRefGoogle Scholar
  20. 20.
    J.J. Hooks, B. Detrick, C. Percopo, C. Hamel, and R. Siraganian, 1989, Development and characterization of monoclonal antibodies directed against the human retinal pigment epithelial cell, Invest. Ophthalmol. Vis. Sci. 30:2106–2113.PubMedGoogle Scholar
  21. 21.
    C.P. Hamel, E. Tsilou, E. Harris, B.A. Pfeffer, J.J. Hooks, B. Detrick, and T.M. Redmond, 1993, A developmentally regulated microsomal protein specific for the pigment epithelium of the vertebrate retina, J. Neurosci. Res. 34:414–425.PubMedCrossRefGoogle Scholar
  22. 22.
    S.A. Vinores, W. Orman. J.J. Hooks, B. Detrick, and P.A. Campochiaro, 1993, Ultrastructural localization of RPE-associated epitopes recognized by monoclonal antibodies in human RPE and their induction in human fibroblasts by vitreous, Graefes Arch. Clin. Exp. Ophthalmol. 231:395–401.PubMedCrossRefGoogle Scholar
  23. 23.
    C.P. Hamel, E. Tsilou, B. A. Pfeffer, J.J. Hooks, B. Detrick, and T.M. Redmond, 1993, Molecular cloning and expression of RPE65, a novel retinal pigment epithelium-specific microsomal protein that is posttranscriptionally regulated in vitro, J. Biol. Chem. 268:15751–15757.PubMedGoogle Scholar
  24. 24.
    C.-O. Båvik, C. Busch, and U. Eriksson, 1992, Characterization of a plasma retinol-binding protein membrane receptor expressed in the retinal pigment epithelium, J. Biol. Chem. 267:23035–23042.PubMedGoogle Scholar
  25. 25.
    C.-O. Båvik, U. Eriksson, R.A. Allen, and P.A. Peterson, 1991, Identification and partial characterization of a retinal pigment epithelial membrane receptor for plasma retinol-binding protein, J. Biol. Chem. 266:14978–14985.PubMedGoogle Scholar
  26. 26.
    C.-O. Båvik, F. Lévy, U Hellman, C. Wernstedt, and U Eriksson, 1993, The retinal pigment epithelial membrane receptor for plasma retinol-binding protein, J. Biol. Chem. 268:20540–20546.PubMedGoogle Scholar
  27. 27.
    E. Tsilou, C.P. Hamel, S. Yu, and T.M. Redmond, 1997, RPE65, the major retinal pigment epithelium microsomal membrane protein associates with phospholipid liposomes, Arch. Biochem. Biophys. 346:21–27.PubMedCrossRefGoogle Scholar
  28. 28.
    A. Nicoletti, D.J. Wong, K. Kawase, L.H. Gibson, T.L. Yang-Feng, J.E. Richards, and D.A. Thompson, 1995, Molecular characterization of the gene encoding an abundant protein specific to the retinal pigment epithelium. Hum. Molec. Genet. 4:641–649.PubMedCrossRefGoogle Scholar
  29. 29.
    S.-Y. Liu, and T.M. Redmond, 1998, Role of the 3’ untranslated region of RPE65 mRNA in the translational regulation of the RPE65 gene: Identification of a specific translation inhibitory element (TIE), Arch. Biochem. Biophys. 357:37–44.PubMedCrossRefGoogle Scholar
  30. 30.
    G. Manes, R. Leducq, J. Kucharczak, A. Pages, C.F. Schmitt-Bernard, and C.P. Hamel, 1998, Rat messenger RNA for the retinal pigment epithelium-specific protein RPE65 gradually accumulates in two weeks from late embryonic days, FEBS Lett. 423:133–137.PubMedCrossRefGoogle Scholar
  31. 31.
    J.-x. Ma, L. Xu, D.K. Lockman, T.M. Redmond, and R.K. Crouch, 1998, Cloning and localization of RPE65 mRNA in salamander cone photoreceptor cells, Biochim. Biophys. Acta, 1443:255–261.PubMedGoogle Scholar
  32. 32.
    C.P. Hamel, N.A. Jenkins, D.J. Gilbert, N.G. Copeland, and T.M. Redmond, 1994, The gene for the retinal pigment epithelium-specific protein RPE65 is localized to human 1p31 and mouse 3, Genomics 20:509–512.PubMedCrossRefGoogle Scholar
  33. 33.
    F. Marlhens, C. Bareil, J.-M. Griffoin, E. Zrenner, P. Amalric, C. Eliaou, S.-Y. Liu, E. Harris, T.M. Redmond, B. Arnaud, M. Claustres, and C.P. Hamel, 1997, Mutations in RPE65 cause Leber’s congenital amaurosis, Nature Genetics 17:139–141.PubMedCrossRefGoogle Scholar
  34. 34.
    S.-m. Gu, D.A. Thompson, C.R. Srisailapathy Srikumari, B. Lorenz, U. Finckh, A. Nicoletti, K.R. Murthy, M. Rathmann, G. Kumaramanickavel, M.J. Denton, and A. Gal, 1997, Mutations in RPE65 cause autosomal recessive childhood-onset severe retinal dystrophy, Nature Genet. 17:194–197.PubMedCrossRefGoogle Scholar
  35. 35.
    H. Morimura, G.A. Fishman, S.A. Grover, A.B. Fulton, E.L. Berson, and T.P. Dryja, 1998, Mutations in the RPE65 gene in patients with autosomal retinitis pigmentosa or Leber congenital amaurosis, Proc. Natl. Acad. Sci. USA 95:3088–3093.PubMedCrossRefGoogle Scholar
  36. 36.
    T.M. Redmond, S. Yu, E. Lee. D. Bok, D. Hamasaki, N. Chen, P. Goletz, J.-X. Ma, R.K. Crouch, and K. Pfeiffer, 1998, RPE65 is necessary for production of 11-cis-Vitamin A in the retinal visual cycle, Nature Genetics 20:344–351.PubMedCrossRefGoogle Scholar
  37. 37.
    W.G. Robison, and T. Kuwabara, 1977, Vitamin A storage and peroxisomes in retinal pigment epithelium and liver, Invest. Ophthalmol. Vis. Sci. 16:1110–1117.PubMedGoogle Scholar
  38. 38.
    J. Heller, and D. Bok, 1976, A specific receptor for retinol-binding protein as detected by the binding of human and bovine retinol-binding protein to pigment epithelial cells, Am. J. Ophthalmol. 81:93–97.PubMedGoogle Scholar
  39. 39.
    D.C. Hood, and P.A. Hock, 1973, Recovery of cone receptor activity in the frog’s isolated retina. Vision Res. 13:1943–1951.PubMedCrossRefGoogle Scholar
  40. 40.
    E.B. Goldstein, and B.M. Wolf, 1973, Regeneration of the green-rod pigment in the isolated frog retina, Vision Res. 13:527–534.PubMedCrossRefGoogle Scholar
  41. 41.
    G.D. Aguirre, V. Baldwin, S. Pearce-Kelling, K. Narfstrom, K. Ray, G.M. Aeland, 1998. Congenital stationary night blindness in the dog: common mutation in the RPE65 gene indicates founder effect, Mol. Vis. 4:23; Scholar
  42. 42.
    J. Bennett, J. Wilson, D. Sun, B. Forbes, and A. Maguire, 1994, Adenovirus vector-mediated in vivo gene transfer into adult murine retina, Invest. Ophthalmol. Vis. Sci. 35:2535–2542.PubMedGoogle Scholar
  43. 43.
    D.M. Sullivan, D.C. Chung, E. Anglade, R.M. Nussenblatt, and K.G. Csaky, 1996, Adenovirus-mediated gene transfer of ornithine aminotransferase in cultured human retinal pigment epithelium, Invest. Ophthalmol. Vis. Sci. 37:766–774.PubMedGoogle Scholar
  44. 44.
    R.R. Ali, M.B. Reichet, A.J. Thrasher, R.J. Levinsky, C. Kinnon, N. Kanuga, D.M. Hunt, S.S. Bhattacharya, 1996, Gene transfer into the mouse retina mediated by an adeno-associated viral vector, Hum. Mot. Genet. 5:591–594.CrossRefGoogle Scholar

Copyright information

© Kluwer Academic / Plenum Publishers 1999

Authors and Affiliations

  • T. Michael Redmond
    • 1
  1. 1.Laboratory of Retinal Cell and Molecular BiologyNational Eye Institute, National Institutes of HealthBethesda

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