Blindness in Usher Syndrome 1B

Myosin VIIa in the Retina
  • David S. Williams
  • Xinran Liu
  • Gordon Vansant
  • Brian Ondek


The turnover of phototransductive membrane is an essential process for the viability of photoreceptor cells. Molecular motors are likely candidates for the trafficking of phototransductive membrane during various stages of its turnover. Our studies of molecular motors in photoreceptor cells and the RPE are aimed at understanding mechanisms involved in phototransductive membrane turnover and the cellular basis of some forms of retinal degeneration. Results described here represent initial studies on the role of myosin VIIa in the retina. Defects in the myosin VIIa, gene have been found to cause forms of Usher syndrome. Myosin VIIa, was localized in the apical processes of the RPE and in the connecting cilium of the photoreceptor cells. In the retinas of shaker-1 mice, which express mutant myosin VIIa, the only identifiable structural defect was the mislocalization of the melanosomes of the RPE. Disk membrane shedding did not appear to be affected. Nevertheless, the localization of myosin VIIa, in the photoreceptor cilium suggests that the protein might be involved in transporting phototransductive membrane to the outer segment.


Retinal Pigment Epithelium Outer Segment Photoreceptor Cell Retinal Degeneration Apical Process 
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.
    Young, R.W. and Bok, D. 1969, Participation of the retinal pigment epithelium in the rod outer segment renewal process, J. Cell Biol. 42:392–403.PubMedCrossRefGoogle Scholar
  2. 2.
    Williams, D.S. and Fisher, S.K. 1987, Prevention of the shedding of rod outer segment disks by detachment from the retinal pigment epithelium, Invest. Ophthalmol. Vis. Sci. 28:184–187.PubMedGoogle Scholar
  3. 3.
    Young, R.W. 1967, The renewal of photoreceptor cell outer segments, J. Cell Biol. 33:61–72.PubMedCrossRefGoogle Scholar
  4. 4.
    Papermaster, D.S., Schneider, B.G., and Besharse, J.C. 1985, Vesicular transport of newly synthesized opsin from the Golgi apparatus toward the rod outer segment, Invest. Ophthalmol. Vis. Sci. 26:1386–1404.PubMedGoogle Scholar
  5. 5.
    Steinberg, R.H., Fisher, S.K., and Anderson, D.H. 1980, Disc morphogenesis in vertebrate photoreceptors, J. Comp. Neurol. 190:501–508.PubMedCrossRefGoogle Scholar
  6. 6.
    Besharse, J.C. and Hollyfield, J.G. 1979, Turnover of mouse photoreceptor outer segments in constant light and darkness, Invest. Ophthalmol. Vis. Sci. 18:1019–1024.PubMedGoogle Scholar
  7. 7.
    Guerin, C.J., Lewis, G.P., Fisher, S.K., and Anderson, D.H. 1993, Recovery of photoreceptor outer segment length and analysis of membrane assembly rates in regenerating primate photoreceptor outer segment, Invest. Ophthalmol. Vis. Sci. 34:175–183.PubMedGoogle Scholar
  8. 8.
    Corless, J.M., Cobbs, W.H., Costello, M.J., and Robertson, J.D. 1976, On the asymmetry of frog retinal rod outer segment disk membranes, Exp. Eye Res. 23:295–324.PubMedCrossRefGoogle Scholar
  9. 9.
    Curcio, C.A., Sloan, K.R., Kalina, R.E., and Hendrickson, A.E. 1990, Human photoreceptor topography, J. Comp. Neurol. 292:497–523.PubMedCrossRefGoogle Scholar
  10. 10.
    Bok, D. and Hall, M.O. 1971, The role of the pigment epithelium in the etiology of inherited retinal dystrophy in the rat, J. Cell Biol. 49:664–682.PubMedCrossRefGoogle Scholar
  11. 11.
    Aguirre, G., Alligood, J., O’Brien, P., and Buyukmihci, N. 1982, Pathogenesis of progressive rod-cone degeneration in miniature poodles, Invest. Ophthalmol. Vis. Sci. 23:610–630.PubMedGoogle Scholar
  12. 12.
    Jansen, H.G. and Sanyal, S. 1984, Development and degeneration of retina in rds mutant mice: electron microscopy, J. Comp. Neurol. 224:71–84.PubMedCrossRefGoogle Scholar
  13. 13.
    Travis, G.H., Brennan, M.B., Danielson, P.E., Kozak, C.A., and Sutcliffe, J.G. 1989, Identification of a photoreceptor-specific mRNA encoded by the gene responsible for retinal degeneration slow (rds), Nature 338:70–73.PubMedCrossRefGoogle Scholar
  14. 14.
    Connell, G., Bascom, R., Molday, L., Reid, D., McInnes, R.R., and Molday, R.S. 1991, Photoreceptor peripherin is the normal product of the gene responsible for retinal degeneration in the rds mouse, Proc. Nat. Acad. Sci. (USA) 88:723–726.CrossRefGoogle Scholar
  15. 15.
    Li, T.S., 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 93:14176–14181.PubMedCrossRefGoogle Scholar
  16. 16.
    Liu, X., Wu, T.-H., Stowe, S., Matsushita, A., Arikawa, K., Naash, M.I., and Williams, D.S. 1997, Defective phototransductive disk membrane morphogenesis in transgenic mice expressing rhodopsin with a mutated N-terminal domain, J. Cell Sci. 110:2589–2597.PubMedGoogle Scholar
  17. 17.
    Clarke, G.A., Rossant, J., and McInnes, R.R. 1998, Rom-1 is required for outer segment morphogenesis and photoreceptor viability, Invest. Opththamol. Vis. Sci. 39:S962.Google Scholar
  18. 18.
    Montell, C. and Rubin, G.M. 1988, The Drosophila ninaC locus encodes two photoreceptor cell specific proteins with domains homologous to protein kinases and the myosin heavy chain head, Cell 52:757–772.PubMedCrossRefGoogle Scholar
  19. 19.
    Matsumoto, H.K., Isono, K., Pye, Q., and Pak, W.L. 1987, Genes encoding cytoskeletal proteins in Drosophila rhabdomeres, Proc. Natl. Acad. Sci. USA. 84:985–989.PubMedCrossRefGoogle Scholar
  20. 20.
    Ng, K.P., Kambara, T., Matsuura, M., Burke, M., and Ikebe, M. 1996, Identification of myosin III as a protein kinase, Biochemistry 35:9392–9399.PubMedCrossRefGoogle Scholar
  21. 21.
    Porter, J.A. and Montell, C. 1993, Distinct roles of the Drosophila ninaC kinase and myosin domains revealed by systematic mutagenesis, J. Cell Biol. 122:601–612.PubMedCrossRefGoogle Scholar
  22. 22.
    Hicks, J.L., Liu, X.R., and Williams, D.S. 1996, Role of the ninac proteins in photoreceptor cell structure: ultrastructure of ninac deletion mutants and binding to actin filaments, Cell Motil. Cytoskel. 35:367–379.CrossRefGoogle Scholar
  23. 23.
    Hicks, J.L. and Williams, D.S. 1992, Distribution of the myosin I-like ninaC proteins in the Drosophila retina and ultrastructural analysis of mutant phenotypes, J. Cell Sci. 101:247–254.PubMedGoogle Scholar
  24. 24.
    Porter, J.A., Hicks, J.L., Williams, D.S., and Montell, C. 1992, Differential localizations of and requirements for the two Drosophila ninaC kinase Imyosins in photoreceptor cells, J. Cell Biol. 116:683–693.PubMedCrossRefGoogle Scholar
  25. 25.
    Porter, J.A., Yu, M., Doberstein, S.K., Pollard, T.D., and Montell, C. 1993, Dependence of calmodulin localization in the retina on the ninaC unconventional myosin, Science 262:1038–1042.PubMedCrossRefGoogle Scholar
  26. 26.
    Arikawa, K., Hicks, J.L., and Williams, D.S. 1990, Identification of actin filaments in the rhabdomeral microvilli of Drosophila photoreceptors, J. Cell Biol. 110:1993–1998.PubMedCrossRefGoogle Scholar
  27. 27.
    Weil, D., Blanchard, S., Kaplan, J., Guilford, P., Gibson, F., Walsh, J., Mburu, P., Varela, A., Levilliers, J., Weston, M.D., Kelley, P.M., Kimberling, W.J., Wagenaar, M., Levi-Acobas, F., Larget-Piet, D., Munnich, A., Steel, K.P., Brown, S.D.M., and Petit, C. 1995, Defective myosin VIIA gene responsible for Usher syndrome type 1B, Nature 374:60–61.PubMedCrossRefGoogle Scholar
  28. 28.
    Liu, X.Z., Hope, C., Walsh, J., Newton, V., Mei, K.X., Liang, C., Xu, L.R., Zhou, J.M., Trump, D., Steel, K.P., Bundey, S., and Brown, S.D.M. 1998, Mutations in the myosin VIIA gene cause a wide phenotypic spectrum including atypical Usher syndrome, Amer. J. Hum. Genet. in press.Google Scholar
  29. 29.
    Gibson, F., Walsh, J., Mburu, P., Varela, A., Brown, K.A., Antonio, M., Beisel, K.W., Steel, K.P., and Brown, S.D.M. 1995, A type VII myosin encoded by mouse deafness gene shaker-1, Nature 374:62–64.PubMedCrossRefGoogle Scholar
  30. 30.
    Liu, X., Vansant, G., Udovichenko, I.P., Wolfrum, U., and Williams, D.S. 1997, Myosin VIIa, the product of the Usher 1B syndrome gene, is concentrated in the connecting cilia of photoreceptor cells, Cell Motil. Cytoskel. 37:240–252.CrossRefGoogle Scholar
  31. 31.
    Hasson, T., Heintzelman, M.B., Santos-Sacchi, J., Corey, D.P., and Mooseker, M.S. 1995, Expression in cochlea and retina of myosin VIIa, the gene product defective in Usher syndrome type 1B, Proc. Natl. Acad. Sci. USA 92:9815–9819.PubMedCrossRefGoogle Scholar
  32. 32.
    El-Amraoui, A., Sahly, I., Picaud, S., Sahel, J., Abitbol, M., and Petit, C. 1996, Human Usher 1B/mouse shaker-Z: the retinal phenotype discrepancy explained by the presence/absence of myosin VIIA in the photoreceptor cells, Hum. Mol. Genet. 5:1171–1178.PubMedCrossRefGoogle Scholar
  33. 33.
    Weston, M.D., Kelley, P.M., Overbeck, L.D., Wagenaar, M., Orten, D.J., Hasson, T., Chen, Z.Y., Corey, D., Mooseker, M., Sumegi, J., Cremers, C., Moller, C., Jacobson, S.G., Gorin, M.B., and Kimberling, W.J. 1996, Myosin VIIa, mutation screening in 189 Usher syndrome type 1 patients, Amer. J. Hum. Genet. 59:1074–1083.PubMedGoogle Scholar
  34. 34.
    Hasson, T., Walsh, J., Cable, J., Mooseker, M.S., Brown, S.D.M., and Steel, K.P. 1997, Effects of shaker 1 mutations on myosin-VIIa protein and mRNA expression, Cell Motil. Cytoskel. 37:127–138.CrossRefGoogle Scholar
  35. 35.
    Liu, X.R., Ondek, B., and Williams, D.S. 1998, Mutant myosin VIIa, causes defective melanosome distribution in the RPE of shaker-1 mice, Nature Genetics 19:117–118.PubMedCrossRefGoogle Scholar
  36. 36.
    Liu, X.-Z., Walsh, J., Mburu, P, KendrickJones, J., Cope, M.J.T.V., Steel, K.P., and Brown, S.D.M. 1997, Mutations in the myosin VIIA gene cause non-syndromic recessive deafness, Nature Genetics 16:188–190.PubMedCrossRefGoogle Scholar
  37. 37.
    Liu, X.-Z., Walsh, J., Tamagawa, Y., Kitamura, K., Nishizawa, M., Steel, K.P., and Brown, S.D.M. 1997, Autosomal dominant non-syndromic deafness caused by a mutation in the myosin VIIA gene, Nature Genetics 17:268–269.PubMedCrossRefGoogle Scholar
  38. 38.
    Weil, D., Kussel, P., Blanchard, S., Levy, G., LeviAcobas, F., Drira, M., Ayadi, H., and Petit, C. 1997, The autosomal recessive isolated deafness, DFNB2, and the Usher 1B syndrome are allelic defects of the myosin-VIIA gene, Nature Genetics 16:191–193.PubMedCrossRefGoogle Scholar
  39. 39.
    Mburu, P., Liu, X.Z., Walsh, J., Saw, D., Jamie, M., Cope, T.V., Gibson, F., Kendrick-Jones, J., Steel, K.P., and Brown, S.D.M. 1997, Mutation analysis of the mouse myosin VIIA deafness gene, Genes Funct. 1:191–203.PubMedGoogle Scholar
  40. 40.
    Bowes, C., Li, T., Danciger, M., Baxter, L.C., Applebury, M.L., and Farber, D.B. 1990, Retinal degeneration in the rd mouse is caused by a defect in the beta subunit of rod cGMP-phosphodiesterase, Nature 347:677–680.PubMedCrossRefGoogle Scholar
  41. 41.
    Carter-Dawson, L.D., La Vail, M.M., and Sidman, R.L. 1978, Differential effect of the rd mutation on rods and cones in the mouse retina, Invest. Ophthalmol. Vis. Sci. 17:489–498.PubMedGoogle Scholar
  42. 42.
    Olsson, J.E., Gordon, J.W., Pawlyk, B.S., Roof, D., Hayes, A., Molday, R.S., Mukai, S., Cowley, G.S., Berson, E.L., and Dryja, T.P. 1992, Transgenic mice with a rhodopsin mutation (Pro23His): a mouse model of autosomal dominant retinitis pigmentosa, Neuron 9:815–30.PubMedCrossRefGoogle Scholar
  43. 43.
    Fishman, G.A., Kumar, A., Joseph, M.E., Torok, N., and Anderson, R.J. 1983, Usher’s syndrome: ophthalmic and neuro-otologic findings suggesting genetic heterogeneity, Arch. Ophthalmol. 101:1367–1374.PubMedGoogle Scholar
  44. 44.
    Murray, R.L. and Dubin, M.W. 1975, The occurrence of actinlike filaments in association with migrating pigment granules in frog retinal pigment epithelium, J. Cell Biol. 64:705–710.PubMedCrossRefGoogle Scholar
  45. 45.
    Burnside, B., Adler, R., and O’Connor, P. 1983, Retinomotor pigment migration in pigment granule transport and cone movement, Invest. Ophthalmol. Vis. Sci. 24:1–15.PubMedGoogle Scholar
  46. 46.
    Troutt, L.L. and Burnside, B. 1989, Role of microtubules in pigment granule migration in teleost retinal pigment epithelial cells, Exp. Eye Res. 48:433–443.PubMedCrossRefGoogle Scholar
  47. 47.
    Cheney, R.E., O’Shea, M.K., Heuser, J.E., Coelho, M.V., Wolenski, J.S., Espreanco, E.M., Forschner, P., Larson, R.E., and Mooseker, M.S. 1993, Brain myosin-V is a two-headed unconventional myosin with motor activity, Cell 75:13–23.PubMedGoogle Scholar
  48. 48.
    Provance, D.W., Wei, M., Ipe, V., and Mercer, J.A. 1996, Cultured melanocytes from dilute mutant mice exhibit dendritic morphology and altered melanosome distribution, Proc. Natl. Acad. Sci. USA 93:14554–14558.PubMedCrossRefGoogle Scholar
  49. 49.
    Nir, I., Cohen, D., and Papermaster, D.S. 1984, Immunocytochemical localization of opsin in the cell membrane of developing rat retinal photoreceptors, J. Cell Biol. 98:1788–1795.PubMedCrossRefGoogle Scholar
  50. 50.
    Besharse, J.C., Forestner, D.M., and Defoe, D.M. 1985, Membrane assembly in retinal photoreceptors. III. Distinct membrane domains of the connecting cilium of developing rods, J. Neurosci. 5:1035–1048.PubMedGoogle Scholar
  51. 51.
    Besharse, J.C. and Horst, C.J. 1990, The photoreceptor connecting cilium: a model for the transition zone, in: Ciliary and flagellar membranes (R.A. Bloodgood, eds.), pp. 409–431, Plenum Press, New York.Google Scholar
  52. 52.
    Williams, D.S., Hallett, M. A., and Arikawa, K. 1992, Association of myosin with the connecting cilium of rod photoreceptors, J. Cell Sci. 103:183–190.PubMedGoogle Scholar
  53. 53.
    Chaitin, M.H. and Coelho, N. 1992, Immunogold localization of myosin in the photoreceptor cilium, Invest. Ophthalmol. Vis. Sci. 33:3103–3108.PubMedGoogle Scholar
  54. 54.
    Beech, P.L., Pagh Roehl, K., Noda, Y., Hirokawa, N., Burnside, B., and Rosenbaum, J.L. 1996, Localization of kinesin superfamily proteins to the connecting cilium of fish photoreceptors, J. Cell Sci. 109:889–97.PubMedGoogle Scholar
  55. 55.
    Muresan, V., BendalaTufanisco, E., Hollander, B.A., and Besharse, J.C. 1997, Evidence for kinesinrelated proteins associated with the axoneme of retinal photoreceptors, Exp. Eye Res. 64:895–903.PubMedCrossRefGoogle Scholar

Copyright information

© Kluwer Academic / Plenum Publishers 1999

Authors and Affiliations

  • David S. Williams
    • 1
  • Xinran Liu
    • 1
  • Gordon Vansant
    • 1
  • Brian Ondek
    • 1
  1. 1.Departments of Pharmacology and NeurosciencesUniversity of California, San Diego School of MedicineLa Jolla

Personalised recommendations