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Recessive mutations in the gene encoding the β–subunit of rod phosphodiesterase in patients with retinitis pigmentosa

Nature Genetics volume 4, pages 130–134 (1993)Cite this article

Abstract

We have found four mutations in the human gene encoding the β–subunit of rod cGMP phosphodiesterase (PDE β) that cosegregate with autosomal recessive retinitis pigmentosa, a degenerative disease of photoreceptors. In one family two affected siblings both carry allelic nonsense mutations at codons 298 and 531. Affected individuals have abnormal rod and cone electroretinograms. PDE β is the second member of the phototransduction cascade besides rhodopsin that is absent or altered as a cause of retinitis pigmentosa, suggesting that other members of this pathway may be defective in other forms of this disease.

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References

  1. Boughman, J.A., Conneally, P.M. & Nance, W.E. Population genetic studies of retinitis pigmentosa. Am. J. hum. Genet. 32, 223–235 (1980).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Bunker, C.H., Berson, E.L., Bromley, W.C., Hayes, R.P. & Roderick, T.H. Prevalence of retinitis pigmentosa in Maine. Am. J. Ophthalmol. 97, 357–365 (1984).

    Article  CAS  PubMed  Google Scholar 

  3. Dryja, T.P., Hahn, L.B., Cowley, G.S., McGee, T.L. & Berson, E.L. Mutation spectrum of the rhodopsin gene among patients with autosomal dominant retinitis pigmentosa. Proc. natn. Acad. Sci. U.S.A. 88, 9370–9374 (1991).

    Article  CAS  Google Scholar 

  4. Sung, C. et al. Rhodopsin mutations in autosomal dominant retinitis pigmentosa. Proc. natn. Acad. Sci. U.S.A. 88, 6481–6485 (1991).

    Article  CAS  Google Scholar 

  5. Sheffield, V.C., Fishman, G.A., Beck, J.S., Kimura, A.E. & Stone, E.M. Identification of novel rhodopsin mutations associated with retinitis pigmentosa by GC-clamped denaturing gradient gel electrophoresis. Am. J. hum. Genet. 49, 699–706 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Inglehearn, C.F. et al. A completed screen for mutations of the rhodopsin gene in a panel of patients with autosomal dominant retinitis pigmentosa. Hum. molec. Genet. 1, 41–45 (1992).

    Article  CAS  PubMed  Google Scholar 

  7. Rosenfeld, P.J. et al. A null mutation in the rhodopsin gene causes rod photoreceptor dysfunction and autosomal recessive retinitis pigmentosa. Nature Genet. 1, 209–213 (1992).

    Article  CAS  PubMed  Google Scholar 

  8. Farrar, G.J. et al. A three-base pair deletion in the peripherin-RDS gene in one form of retinitis pigmentosa. Nature 354, 478–480 (1991).

    Article  CAS  PubMed  Google Scholar 

  9. Kajiwara, K. et al. Mutations in the human retinal degeneration slow gene in autosomal dominant retinitis pigmentosa. Nature 354, 480–483 (1991).

    Article  CAS  PubMed  Google Scholar 

  10. Nichols, B.E. et al. Butterfly-shaped pigment dystrophy of the fovea caused by a point-mutation in codon 167 of the RDS gene. Nature Genet. 3, 202–207 (1993).

    Article  CAS  PubMed  Google Scholar 

  11. Wells, J. et al. Mutations in the human retinal degeneration slow (RDS) gene can cause either retinitis pigmentosa or macular dystrophy. Nature Genet. 3, 213–217 (1993).

    Article  CAS  PubMed  Google Scholar 

  12. Kajiwara, K., Sandberg, M.A., Berson, E.L. & Dryja, T.P. A null mutation in the human peripherin/RDS gene in a family with autosomal dominant retinitis punctata albescens. Nature Genet. 3, 208–212 (1993).

    Article  CAS  PubMed  Google Scholar 

  13. Bowes, C. et al. Retinal degeneration in the rd mouse is caused by a defect in the beta subunit of rod cGMP-phosphodiesterase. Nature 347, 677–680 (1990).

    Article  CAS  PubMed  Google Scholar 

  14. Pittler, S.J. & Baehr, W. Identification of a nonsense mutation in the rod photoreceptor cGM P phosphodiesterase beta subunit gene of the rd mouse. Proc. natn. Acad. Sci. U.S.A. 88, 8322–8326 (1991).

    Article  CAS  Google Scholar 

  15. Orita, M., Suzuki, Y., Sekiya, T. & Hayashi, K. Rapid and sensitive detection of point mutations and DMA polymorphisms using polymerase chain reaction. Genomics 5, 874–879 (1989).

    Article  CAS  PubMed  Google Scholar 

  16. Charbonneau, H., Beier, N., Walsh, K.A. & Beavo, J.A. Identification of a conserved domain among cyclic nucleotide phosphodiesterasesfrom diverse species. Proc. natn. Acad. Sci. U.S.A. 83, 9308–9312 (1986).

    Article  CAS  Google Scholar 

  17. Charbonneau, H. et al. Identification of a noncatalytic cGMP-binding domain conserved in both the cGMP-stimulated and photoreceptor cyclic nucleotide phosphodiesterases. Proc. natn. Acad. Sci. U.S.A. 87, 288–292 (1990).

    Article  CAS  Google Scholar 

  18. Weber, B. et al. Genomic organization and complete sequence of the human gene encoding the beta subunit of the cGMP phosphodiesterase and its localization to 4p16.3. Nucl. Acids Res. 19, 6263–6268 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Collins, C. et al. The human beta subunit of rod photoreceptor cGMP phosphodiesterase: complete retinal cDNA sequence and evidence for expression in brain. Genomics 13, 698–704 (1992).

    Article  CAS  PubMed  Google Scholar 

  20. Li, T., Volpp, K. & Applebury, M.L. Bovine cone photoreceptor cGMP phosphodiesterase structure deduced from a cDNA clone. Proc. natn. Acad. Sci. U.S.A. 87, 293–297 (1990).

    Article  CAS  Google Scholar 

  21. Sandberg, M.A., Miller, S. & Berson, E.L. Rod electroretinograms in an elevated cyclic guanosine monophosphate-type human retinal degeneration. Invest. ophthalmol. Vis. Sci. 31, 2283–2287 (1990).

    CAS  PubMed  Google Scholar 

  22. Riess, O., Noerremoelle, A., Weber, B., Musarella, M.A. & Hayden, M.R. The search for mutations in the gene for the beta subunit of the cGMP phosphodiesterase (PDEB) in patients with autosomal recessive retinitis pigmentosa. Am. J. hum. Genet. 51, 755–762 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Keeler, C. The inheritance of a retinal abnormality in white mice. Proc. natn. Acad. Sci. U.S.A. 10, 329–333 (1924).

    Article  CAS  Google Scholar 

  24. Keeler, C.E. On the occurrence in the house mouse of a mendelizing structural defect of the retina producing blindness. Proc. natn. Acad. Sci. U.S.A. 12, 255–258 (1926).

    Article  CAS  Google Scholar 

  25. Keeler, C.E. Retinal degeneration in the mouse is rodless retina. J. Hered. 57, 47–50 (1966).

    Article  CAS  PubMed  Google Scholar 

  26. Farber, D.B. & Lolley, R.N. Enzymic basis for cyclic GMP accumulation in degenerative photoreceptor cells of mouse retina. J. cyclic nucleotide Res. 2, 139–148 (1976).

    CAS  PubMed  Google Scholar 

  27. Farber, D.B. & Lolley, R.N. Cyclic guanosine monophosphate: elevation in degenerating photoreceptor cells of the C3H mouse retina. Science 186, 449–451 (1974).

    Article  CAS  PubMed  Google Scholar 

  28. Lolley, R.N., Farber, D.B., Rayborn, M.E. & Hollyfield, J.G. Cyclic GMP accumulation causes degeneration of photoreceptor cells: simulation of an inherited disease. Science 196, 664 (1977).

    Article  CAS  PubMed  Google Scholar 

  29. Ulshafer, R.J., Garcia, C.A. & Hollyfield, J.G. Sensitivity of photoreceptors to elevated levels of cGMP in the human retina. Invest. ophthalmol. Vis. Sci. 19, 1236–1241 (1980).

    CAS  PubMed  Google Scholar 

  30. Ferrendelli, J.A. & Cohen, A.I. The effects of light and dark adaptation on the levels of cyclic nucleotides in retinas of mice heterozygous for a gene for photoreceptor dystrophy. Biochem. biophys. Res. Commun. 73, 421–426 (1976).

    Article  CAS  PubMed  Google Scholar 

  31. Doshi, M., Voaden, M.J. & Arden, G.B. Cyclic GMP in the retinas of normal mice and those heterozygous for early-onset photoreceptor dystrophy. Exp. eye Res. 41, 61–65 (1985).

    Article  CAS  PubMed  Google Scholar 

  32. Yomaki, K., Tsuda, M. & Shinohara, T. The sequence of human retinal S-antigen reveals similarities with alpha-transducin. FEBS Lett. 234, 39–43 (1988).

    Article  Google Scholar 

  33. Lerea, C.L., Bunt-Milam, A.H. & Hurley, J.B. Alpha transducin is present in blue-, green-, and red-sensitive cone photoreceptors in the human retina. Neuron 3, 367–376 (1989).

    Article  CAS  PubMed  Google Scholar 

  34. Kaupp, U.B. et al. Primary structure and functional expression from complementary DNA of the rod photoreceptor cyclic GMP-gated channel. Nature 342, 762–766 (1989).

    Article  CAS  PubMed  Google Scholar 

  35. Pittler, S.J. et al. Primary structure and chromosomal localization of human and mouse rod photoreceptor cGMP-gated cation channel. J. biol. Chem. 267, 6257–6262 (1992).

    CAS  PubMed  Google Scholar 

  36. Pittler, S.J. et al. Molecular characterization of human and bovine rod photoreceptor cGMP phosphodiesterase alpha subunit and chromosomal localization of the human gene. Genomics 6, 272–283 (1990).

    Article  CAS  PubMed  Google Scholar 

  37. Tuteja, N. et al. Isolation and characterization of cDNA encoding the gamma-subunit of cGMP phosphodiesterase in human retina. Gene 88, 227–232 (1990).

    Article  CAS  PubMed  Google Scholar 

  38. Cotran, P.R., Bruns, G.A., Berson, E.L. & Dryja, T.P. Genetic analysis of patients with retinitis pigmentosa using a cloned cDNA probe for the human gamma subunit of cyclic GMP phosphodiesterase. Exp. eye Res. 53, 557–564 (1991).

    Article  CAS  PubMed  Google Scholar 

  39. Dizhoor, A.M. et al. Recoverin: a calcium-sensitive activator of retinal rod guanylate cyclase. Science 251, 915–922 (1991).

    Article  CAS  PubMed  Google Scholar 

  40. Lorenz, W. et al. The receptor kinase family: primary structure of rhodopsin kinase reveals similarities to the beta-adrenergic receptor kinase. Proc. natn. Acad. Sci. U.S.A. 88, 8715–8719 (1991).

    Article  CAS  Google Scholar 

  41. Shyjan, A.W. et al. Molecular cloning of a retina-specific membrane guanylyl cyclase. Neuron 9, 727–737 (1992).

    Article  CAS  PubMed  Google Scholar 

  42. Kunkle, L.M., Smith, K.D. & Boyer, S.H. Analysis of human Y-chromosome-specific reiterated DNA in chromosome variants. Proc. natn. Acad. Sci. U.S.A. 74, 1245–1249 (1977).

    Article  Google Scholar 

  43. Riess, O., et al. Exclusion of DNA changes in the beta subunit of the cGMP phosphodiesterase gene as the cause for Huntington's disease. Nature Genetics 1, 104–108 (1992).

    Article  CAS  PubMed  Google Scholar 

  44. Yandell, D.W. & Dryja, T.P. in Cold Spring Harbor Symposium Series: Cancer Cells 7- Molecular Diagnostics of Human Cancer Cells (eds Furth, M. & Greaves, M.) 223–227 (Cold Spring Harbor Laboratory, New York, 1989).

    Google Scholar 

  45. Berson, E.L., Gouras, P. & Gunkel, R.D. Rod responses in retinitis pigmentosa, dominantly inherited. Arch. Ophthalmol. 80, 58–67 (1968).

    Article  CAS  PubMed  Google Scholar 

  46. Berson, E.L., Sandberg, M.A., Rosner, B.R., Birch, D.G. & Hanson, A.H. Natural course of retinitis pigmentosa over a three-year interval. Am. J. Ophthal. 99, 240–251 (1985).

    Article  CAS  PubMed  Google Scholar 

  47. Andreasson, S.O.L., Sandberg, M.A. & Berson, E.L. Narrow-band filtering for monitoring low-amplitude cone electroretinograms in retinitis pigmentosa. Am. J. Ophthal. 105, 500–503 (1988).

    Article  CAS  PubMed  Google Scholar 

  48. Suber, M.L. et al. Irishsetter dogs affected with rod/cone dysplasia contain a nonsense mutation in the rod cGMP phosphodiesterase β-subunit gene. Proc. natn. Acad. Sci. U.S.A. 90, 3968–3972 (1993).

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Berman-Gund Laboratory for the Study of Retinal Degenerations and the Howe Laboratory of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, Massachusetts, 02114, USA

    Margaret E. McLaughlin, Michael A. Sandberg, Eliot L. Berson & Thaddeus P. Dryja

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  1. Margaret E. McLaughlin
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  3. Eliot L. Berson
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  4. Thaddeus P. Dryja
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McLaughlin, M., Sandberg, M., Berson, E. et al. Recessive mutations in the gene encoding the β–subunit of rod phosphodiesterase in patients with retinitis pigmentosa. Nat Genet 4, 130–134 (1993). https://doi.org/10.1038/ng0693-130

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