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

We have found four mutations in the human gene encoding the −subunit of rod cGMP phosphodiesterase (PDE ) 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 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.

1. Boughman, J.A., Conneally, P.M. & Nance, W.E. Population genetic studies of retinitis pigmentosa. Am. J. hum. Genet. 32, 223−235 (1980). | PubMed  | ISI | ChemPort |
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). | PubMed  | ISI | ChemPort |
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). | ChemPort |
4. Sung, C. et al. Rhodopsin mutations in autosomal dominant retinitis pigmentosa. Proc. natn. Acad. Sci. U.S.A. 88, 6481−6485 (1991). | ChemPort |
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). | PubMed  | ISI | ChemPort |
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). | PubMed  | ChemPort |
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 | PubMed  | ISI | ChemPort |
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 | PubMed  | ISI | ChemPort |
9. Kajiwara, K. et al. Mutations in the human retinal degeneration slow gene in autosomal dominant retinitis pigmentosa. Nature 354, 480−483 (1991). | Article | PubMed  | ISI | ChemPort |
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 | PubMed  | ISI | ChemPort |
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 | PubMed  | ISI | ChemPort |
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 | PubMed  | ISI | ChemPort |
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 | PubMed  | ISI | ChemPort |
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). | ChemPort |
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). | PubMed  | ISI | ChemPort |
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). | ChemPort |
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). | ChemPort |
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). | PubMed  | ISI | ChemPort |
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). | PubMed  | ISI | ChemPort |
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). | ChemPort |
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). | PubMed  | ISI | ChemPort |
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). | PubMed  | ISI | ChemPort |
23. Keeler, C. The inheritance of a retinal abnormality in white mice. Proc. natn. Acad. Sci. U.S.A. 10, 329−333 (1924).
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).
25. Keeler, C.E. Retinal degeneration in the mouse is rodless retina. J. Hered. 57, 47−50 (1966). | PubMed  | ISI | ChemPort |
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). | PubMed  | ISI | ChemPort |
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). | PubMed  | ISI | ChemPort |
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). | PubMed  | ISI | ChemPort |
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). | PubMed  | ISI | ChemPort |
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). | PubMed  | ISI | ChemPort |
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). | PubMed  | ISI | ChemPort |
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 | PubMed  | ISI | ChemPort |
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 | PubMed  | ISI | ChemPort |
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 | PubMed  | ISI | ChemPort |
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). | PubMed  | ISI | ChemPort |
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). | PubMed  | ISI | ChemPort |
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). | PubMed  | ISI | ChemPort |
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). | PubMed  | ISI | ChemPort |
39. Dizhoor, A.M. et al. Recoverin: a calcium-sensitive activator of retinal rod guanylate cyclase. Science 251, 915−922 (1991). | PubMed  | ISI | ChemPort |
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). | ChemPort |
41. Shyjan, A.W. et al. Molecular cloning of a retina-specific membrane guanylyl cyclase. Neuron 9, 727−737 (1992). | PubMed  | ISI | ChemPort |
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). | ChemPort |
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). | PubMed  | ISI | ChemPort |
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). | ChemPort |
45. Berson, E.L., Gouras, P. & Gunkel, R.D. Rod responses in retinitis pigmentosa, dominantly inherited. Arch. Ophthalmol. 80, 58−67 (1968). | PubMed  | ISI | ChemPort |
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). | PubMed  | ISI | ChemPort |
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). | PubMed  | ISI | ChemPort |
48. Suber, M.L. et al. Irishsetter dogs affected with rod/cone dysplasia contain a nonsense mutation in the rod cGMP phosphodiesterase -subunit gene. Proc. natn. Acad. Sci. U.S.A. 90, 3968−3972 (1993). | ChemPort |

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