Guanylyl Cyclase Gene is the Disease Locus in the rd Chicken

A Model for Leber Congenital Amaurosis, Type 1
  • Susan L. Semple-Rowland


The first description of the retinal degeneration (rd) chicken appeared in the literature in 1980. From the early 1980s to 1991, Ulshafer and his colleagues carried out detailed electrophysiological, morphological, and biochemical analyses of the retinas of these animals, the results of which provided a comprehensive description of the pathology of this retinal degenerative disease, and the first clues concerning the identity of the rd gene. In 1990, we embarked on a series of molecular studies that would eventually lead to the identification of the rd gene in 1998. As a result of the tireless efforts of many individuals, the rd chicken is now recognized as a model for Leber congenital amaurosis, Type 1, a devastating human disease that causes blindness in newborn infants. With the identity of the rd gene in hand, it seems appropriate to review the nearly two decades of research that has been conducted on this model, research that has provided a firm foundation for our current efforts to restore sight in these animals using somatic gene therapy.


Retinal Pigment Epithelium Outer Segment Guanylate Cyclase Photoreceptor Cell Guanylyl Cyclase 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    K.M. Cheng, R.N. Shoffner, K.N. Gelatt, G.G. Gum, J.S. Otis, and J.J. Bitgood, 1980, An autosomal recessive blind mutant in chickens, Poultry Sci. 59:2179–2182.Google Scholar
  2. 2.
    R.J. Ulshafer, C. Allen, W.W. Dawson, and E.D. Wolf, 1984, Hereditary retinal degeneration in the Rhode Island Red chicken. I. Histology and ERG. Exp. Eye Res. 39:125–135.PubMedCrossRefGoogle Scholar
  3. 3.
    I. MacLachlan, J. Nimpf, H.B. White, III, W.J. Schneider, 1993, Riboflavinuria in the rd chicken. 5’-splice site mutation in the gene for riboflavin-binding protein. J. Biol. Chem. 268:23222–23226.PubMedGoogle Scholar
  4. 4.
    S.W. Rabkin and K.M. Cheng, 1992, A genetic abnormality of cardiac myocytes from the blind mutant (RC) chick heart: abnormalities of cardiac structure and choline transport. Basic Res. Cardiol. 87:610–617.PubMedCrossRefGoogle Scholar
  5. 5.
    S. Cerruti Sola, M. Castagnaro, and K.M. Cheng, 1997, Histological changes caused by the rc mutation in chickens. J. Comp. Pathol. 116:329–338.PubMedCrossRefGoogle Scholar
  6. 6.
    W.W. Dawson, R.J. Ulshafer, R. Parmer, and N.R. Lee, 1990, Receptor potentials in the normal and retinal degenerate (rd) chick. Clin. Vision Sci. 5:285–292.Google Scholar
  7. 7.
    G.S. Brindley and A.R. Gardner-Medwin, 1966, The origin of the ERP of the retina. J. Physiol. 182:185–194.PubMedGoogle Scholar
  8. 8.
    R.A. Cone, 1967, Early receptor potential: photoreversible charge displacement in rhodopsin. Science, 155:1128–1131.PubMedCrossRefGoogle Scholar
  9. 9.
    E.B. Goldstein and E.L. Berson, 1969, Cone dominance of the human early receptor potential. Nature, 222:1272–1273.PubMedCrossRefGoogle Scholar
  10. 10.
    E.B. Goldsterin, 1969, Contribution of cones in the early receptor potential in the rhesus monkey. Nature, 222:1273–1274.CrossRefGoogle Scholar
  11. 11.
    R.J. Ulshafer and M.B. Heaton, 1989, Axonal transport and central visual projections of ganglion cells in congenitally blind chickens. Curr. Eye Res. 8:321–326.PubMedGoogle Scholar
  12. 12.
    R.J. Ulshafer and C.B. Allen, 1985, Hereditary retinal degeneration in the Rhode Island Red chicken: Ultrastructural analysis. Exp. Eye Res. 40:865–877.PubMedCrossRefGoogle Scholar
  13. 13.
    S.L. Semple-Rowland, 1991, Expression of glial fibrillary acidic protein by Müller cells in rd chick retina. J. Comp. Neurol. 305:582–590.PubMedCrossRefGoogle Scholar
  14. 14.
    R.J. Ulshafer and C.B. Allen, 1985, Ultrastructural changes in the retinal pigment epithelium of congenitally blind chickens. Curr. Eye Res. 4:1009–1021.PubMedGoogle Scholar
  15. 15.
    C.B. Allen, R.J. Ulshafer, E.A. Ellis, and J.C. Woodard, 1987, Scanning electron microscopic analysis of intraocular ossification in advanced retinal disease. Scanning Microscopy, 1:233–239.PubMedGoogle Scholar
  16. 16.
    K.C. Kelley, R.J. Ulshafer, and E.A. Ellis, 1987, Intraocular ossification in the rd chicken. Avian Pathol. 16:189–197.PubMedGoogle Scholar
  17. 17.
    M. Yanoff and B.S. Fine, 1975, Ocular Pathology, A Text and Atlas, pp. 74–75, Harper and Row, Maryland.Google Scholar
  18. 18.
    J.S. Penn and T.P. Williams, 1986, Photostasis: regulation of daily photon-catch by rat retinas in response to various cyclic illuminances. Exp. Eye Res. 43:915–928.PubMedCrossRefGoogle Scholar
  19. 19.
    S.L. Semple-Rowland and W.W. Dawson, 1987, Cyclic light intensity threshold for retinal damage in albino rats raised under 6 lx. Exp. Eye Res. 44:643–661.PubMedCrossRefGoogle Scholar
  20. 20.
    B. Morjaria and M.J. Voaden, 1979, The uptake of [3H]2-deoxy glucose by light-and dark-adapted rat retinas in vivo. J. Neurochem. 32:1881–1883.PubMedCrossRefGoogle Scholar
  21. 21.
    S.S. Goldman and P. Witkovsky, 1986, Glycogen metabolism in an amphibian retina. Exp. Eye Res. 43:267–272.PubMedCrossRefGoogle Scholar
  22. 22.
    N.J. Ruth, R.J. Ulshafer, and K.C. Kelly, 1985, Depressed glucose utilization in the rd chicken retina. Invest. Ophthalmol. Vis. Sci. (Suppl) 26:62.Google Scholar
  23. 23.
    N.J. Ruth, 1991, Cyclic Nucleotides in the (rd) Retinal Degenerate Chicken Retina. Ph.D. dissertation, University of Florida, Gainesville, FL.Google Scholar
  24. 24.
    B. Burnside and B. Nagle, 1983, Retinomoter movements of photoreceptors and retinal pigment epithelium: mechanisms and regulation. Prog. Retinal Res. 2:67–109.CrossRefGoogle Scholar
  25. 25.
    R.J. Ulshafer, D.M. Sherry, R. Dawson, Jr., and D.R. Wallace, 1990, Excitatory amino acid involvement in retinal degeneration. Brain Res. 531:350–354.PubMedCrossRefGoogle Scholar
  26. 26.
    J. Sattayasai, J. Zappia, and D. Ehrlich, 1989, Differential effects of excitatory amino acids on photoreceptors of the chick retina: an electron-microscopical study using the zinc-iodide-osmium technique. Vis. Neurosci. 2:237–45.PubMedCrossRefGoogle Scholar
  27. 27.
    C.D.B. Bridges, R.A. Alvarez, S-L. Fong, G.I. Liou, and R.J. Ulshafer, 1987, Rhodopsin, vitamin A, and interstitial retinol-binding protein in the rd chicken. Invest. Ophthalmol. Vis. Sci. 28:613–617.PubMedGoogle Scholar
  28. 28.
    R.J. Ulshafer, G. Adamus, E. Clausnitzer, and P.A. Hargrave, 1990, Rhodopsin in normal and rd chick retinas. Invest. Ophthalmol. Vis. Sci. (suppl) 31:546.Google Scholar
  29. 29.
    R.J. Ulshafer, E.L. Clausnitzer, D.M. Sherry, A. Szel, and P. Rohlich, 1990, Immunocytochemical identification of outer segment proteins in the rd chicken. Exp. Eye Res. 51:209–216.PubMedCrossRefGoogle Scholar
  30. 30.
    S.L. Semple-Rowland and D.A. Green, 1994, Molecular and biochemical analyses of iodopsin in rd chick retina. Invest. Ophthalmol. Vis. Sci. 35:2550–2557. (also see erratum in Invest. Ophthalmol. Vis. Sci. 35:3126).PubMedGoogle Scholar
  31. 31.
    P. Rohlich and A. Szel, 1993, Binding sites of photoreceptor-specific antibodies COS-1, OS-2, and AD. Curr. Eye Res. 12:935–944.PubMedGoogle Scholar
  32. 32.
    Y. Fukada, K. Kokame, T. Okano, Y. Shichida, T. Yoshizawa, J.H. McDowell, P.A. Hargrave, and K. Palczewski, 1990, Phosphorylation of iodopsin, chicken red-sensitive cone visual pigment. Biochemistry, 29:10102–10106.PubMedCrossRefGoogle Scholar
  33. 33.
    T.A. Shuster and D.B. Farber, 1986, Rhodopsin phosphorylation in developing normal and degenerative mouse retinas. Invest Ophthalmol. Vis. Sci. 27:264–268.PubMedGoogle Scholar
  34. 34.
    K. Palczewski, D.B. Farber, and P.A. Hargrave, 1991, Elevated level of protein phosphatase 2A activity in retinas of rd mice. Exp. Eye Res. 53:101–105.PubMedCrossRefGoogle Scholar
  35. 35.
    S.Y. Schmidt, U.P. Andley, C.A. Heth, and J. Miller, 1986, Deficiency in light-dependent opsin phosphorylation in Irish setters with rod-cone dysplasia. Invest. Ophthalmol. Vis. Sci. 27:1551–1559.PubMedGoogle Scholar
  36. 36.
    D.J. Takemoto, J. Cunnick, and L.J. Takemoto, 1986, Reduced rhodopsin phosphorylation during retinal dystrophy. Biochem. Biophys. Res. Comm. 135:1022–1028.PubMedCrossRefGoogle Scholar
  37. 37.
    R.J. Ulshafer, C.A. Garcia, and J.G. Hollyfield, 1980, Sensitivity of photoreceptors to elevated levels of cGMP in the human retina. Invest. Ophthalmol. Vis. Sci. 19:1236–41.PubMedGoogle Scholar
  38. 38.
    D.B. Farber and R.N. Lolley, 1974, Cyclic guanosine monophosphate: elevation in degenerating photoreceptor cells of the C3H mouse retina. Science, 186:449–451.PubMedCrossRefGoogle Scholar
  39. 39.
    G. Aguirre, D. Farber, R. Lolley, R.T. Fletcher, and G.J. Chader, 1978, Rod-cone dysplasia in Irish setters: a defect in cyclic GMP metabolism in visual cells. Science, 201:1133–1134.CrossRefGoogle Scholar
  40. 40.
    S.L. Semple-Rowland, N.R. Lee, J.P. Van Hooser, K. Palczewski, and W. Baehr, 1998, A null mutation in the photoreceptor guanylate cyclase gene causes the retinal degeneration chicken phenotype. Proc. Natl. Acad. Sci. USA, 95:1271–1276.PubMedCrossRefGoogle Scholar
  41. 41.
    K. Meller and W. Tetzlaff, 1976, Scanning electron microscopic studies on the development of the chick retina. Cell Tiss. Res. 170:145–159.CrossRefGoogle Scholar
  42. 42.
    S.L. Semple-Rowland and H. van der Wel, 1992, Visinin: biochemical and molecular comparisons in normal and rd chick retina. Biochem. Biophys. Res. Commun. 183:456–461.PubMedCrossRefGoogle Scholar
  43. 43.
    S.L. Semple-Rowland and D.A. Green, 1994, Molecular characterization of the a’-subunit of cone photoreceptor cGMP phosphodiesterase in normal and rd chicken. Exp. Eye Res. 59:365–372.PubMedCrossRefGoogle Scholar
  44. 44.
    S. Kawamura, O. Kuwata, M. Yamada, S. Matsuda, O. Hisatomi, and F. Tokunaga, 1996, Photoreceptor protein s26, a cone homologue of S-modulin in frog retina. J. Biol. Chem. 271:21359–21364.PubMedCrossRefGoogle Scholar
  45. 45.
    A. Polans, W. Baehr, and K. Palczewski, 1996, Turned on by Ca2+! The physiology and pathology of Ca2+-binding proteins in the retina. Trends Neurosci., 19:547–554.PubMedCrossRefGoogle Scholar
  46. 46.
    W.A. Gorczyca, A.S. Polans, I. Surgucheva, I. Subbaraya, W. Baehr, and K. Palczewski, 1995, Guanylyl cyclase activating protein. A calcium-sensitive regulator of phototransduction. J. Biol. Chem. 270:22029–22036.PubMedCrossRefGoogle Scholar
  47. 47.
    A.M. Dizhoor, E.V. Olshevskaya, W.J. Henzel, S.C. Wong, J.T. Stults, I. Ankoudinova, and J.B. Hurley, 1995, Cloning, sequencing, and expression of a 24-kDa Ca(2+)-binding protein activating photoreceptor guanylyl cyclase. J. Biol. Chem. 270:25200–25206.PubMedCrossRefGoogle Scholar
  48. 48.
    K. Palczewski, I. Subbaraya, W.A. Gorczyca, B.S. Helekar, C.C. Ruiz, H. Ohguro, J. Huang, X. Zhao, J.W. Crabb, R.S. Johnson, K.A. Walsh, M.P. Gray-Keller, P.B. Detwiler, and W. Baehr, 1994, Molecular cloning and characterization of retinal photoreceptor guanylyl cyclase-activating protein. Neuron 13:395–404.PubMedCrossRefGoogle Scholar
  49. 49.
    S.L. Semple-Rowland, W.A. Gorczyca, J. Buczylko, B.S. Helekar, C.C. Ruiz, I. Subbaraya, K. Palczewski, and W. Baehr, 1996, Expression of GCAP1 and GCAP2 in the retinal degeneration (rd) mutant chicken retina. FEBS Lett. 385:47–52.PubMedCrossRefGoogle Scholar
  50. 50.
    A.W. Shyjan, F.J. de Sauvage, N.A. Gillett, D.V. Goeddel, and D.G. Lowe, 1992, Molecular cloning of a retina-specific membrane guanylyl cyclase. Neuron 9:727–737.PubMedCrossRefGoogle Scholar
  51. 51.
    D.G. Lowe, A.M. Dizhoor, K. Liu, Q. Gu, M. Spencer, R. Laura, L. Lu, and J.B. Hurley, 1995, Cloning and expression of a second photoreceptor-specific membrane retina guanylyl cyclase (RetGC), RetGC-2. Proc. Natl. Acad. Sci. USA, 92:5535–5539.PubMedCrossRefGoogle Scholar
  52. 52.
    R.M. Goraczniak, T. Duda, A. Sitaramayya, and R.K. Sharma, 1994, Structural and functional characterization of the rod outer segment membrane guanylate cyclase. Biochem. J. 302:455–461.PubMedGoogle Scholar
  53. 53.
    R.-B. Yang, D.C. Foster, D.L. Garbers, and H.-J. Fulle, 1995, Two membrane forms of guanylyl cyclase found in the eye. Proc. Natl. Acad. Sci. USA, 92:602–606.PubMedCrossRefGoogle Scholar
  54. 54.
    R.-B. Yang, and D.L. Garbers, 1997, Two eye guanylyl cyclases are expressed in the same photoreceptor cells and form homomers in preference to heteromers. J. Biol. Chem. 272:13738–13742.PubMedCrossRefGoogle Scholar
  55. 55.
    I. Perrault, J.M. Rozet, P. Calvas, S. Gerber, A. Camuzat, H. Dollfus, S. Chatelin, E. Souied, I. Ghazi. C. Leowski, M. Bonnemaison, D. Le Paslier, J. Frezal, J.-L. Dufier, S. Pittler, A. Munnich, and J. Kaplan. 1996, Retinal-specific guanylate cyclase gene mutations in Leber’s congenital amaurosis. Nat. Genet. 14:461–464.PubMedCrossRefGoogle Scholar

Copyright information

© Kluwer Academic / Plenum Publishers 1999

Authors and Affiliations

  • Susan L. Semple-Rowland
    • 1
  1. 1.Department of NeuroscienceUniversity of Florida Brain InstituteGainesville

Personalised recommendations