Abstract
Retinitis pigmentosa (RP) constitutes a group of genetically heterogeneous progressive photore-ceptor degenerations leading to blindness and affecting 50,000–100,000 people in the U.S. alone. Over 20 different RP loci have been mapped1, of which six have been identified. Three of these encode members of the rod photoreceptor visual transduction cascade2: rhodopsin3, the rod cGMP-gated cation channel α subunit4, and the β subunit of cGMP-phosphodiesterase (PDEB)5. As null mutations in PDEB cause some cases of RP and since both α and β subunits are required for full phosphodiesterase activity, we examined the gene encoding the α subunit of cGMP phosphodiesterase (PDEA) in 340 unrelated patients with RP. We found three point mutations in PDEA in affected members of two pedigrees with recessive RP. Each mutation alters an essential functional domain of the encoded protein and likely disrupts its catalytic function. PDEA is the seventh RP gene identified, highlighting the extensive genetic heterogeneity of the disorder and encouraging further investigation into the role of other members of the phototransduction cascade in RP.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Dryja, T.P.R. & Li, T. Molecular genetics of retinitis pigmentosa. Hum. molec. Genet. 4, 1739–1743 (1995).
Stryer, L. Cyclic GMP cascade of vision. Ann. Rev. Neurosci. 9, 87–119 (1986).
Dryja, T.P. et al. A point mutation of the rhodopsin gene in one form of retinitis pigmentosa. Nature 343, 364–366 (1990).
Dryja, T.R., Finn, J.T., Peng, Y.W., McGee, T.L., Berson, E.L. & Yau, K.W. Mutations in the gene encoding the a subunrt of the rod cGMP-gated channel in autosomal recessive retinitis pigmentosa. Proc. natn. Acad. Sci. U.S.A 92, 10177–10181 (1995).
McLaughlin, M.E., Sandberg, M.A., Berson, E.L & Dryja, T.P. Recessive mutations in the gene encoding the β-subunit of rod phosphodiesterase in patients with retinitis pigmentosa. Nature Genet. 4, 130–134 (1993).
Pittler, S.J. et al. Molecular characterization of human and bovine rod photoreceptor cGMP phosphodiesterase a-subuntt and chromosomal localization of the human gene. Genomics 6, 272–283 (1990).
Orita, M., Iwahana, H., Kanazawa, H., Hayashi, K. & Sekiya, T. Detection of polymorphisms of human DMA by gel electrophoresis as single-strand conformation polymorphisms. Proc. natn. Acad. Sci. U.S.A. 86, 2766–2770 (1989).
Yandell, D.W. & Dryja, T.P. Direct genomic sequence of alleles at the human retinoblastoma locus: application to cancer diagnosis and genetic counseling. In Cold Spring Harbor Symposium Series: Cancer Cells 7 — Molecular Diagnostics of Human Cancer (eds Furth, M. & Greaves, M.) 223–227 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, 1989).
Berson, E.L. Retinitis pigmentosa. The Friedenwald Lecture. Invest. Ophthamol. Vis. Sci. 34, 1659–1676 (1993).
Charbonneau, H., Beier, N., Walsh, K.A. & Beavo, J.A. Identification of a conserved domain among cyclic nucleotide phosphodiesterases from diverse species. Proc. natn. Acad. Sci. U.S.A 83, 9308–9312 (1986).
Ong, O.C., Ota, I.M., Clarke, S. & Fung, B.K. The membrane binding domain of rod cGMP phosphodiesterase is posttranslationally modified by methyl esterification at a C-terminal cysteine. Proc. natn. Acad. Sci. U.S.A. 86, 9238–9242 (1989).
Ovchinnikpv, Y.A. et al. Cyclic GMP phosphodiesterase from bovine retina. Amino acid sequence of the α-subunit and nucleotide sequence of the corresponding cDNA. FEBS Lett. 223, 169–173 (1987).
Baehr, W., Champagne, M.S., Lee, A.K. & Pittler, S.J. Complete cDNA sequences of mouse rod photoreceptor cGMP phosphodiesterase a- and B-subunrts, and identificaton of β′-, a putative β-subunit isozyme produced by alternative splicing of the β-subunit gene. FEBS Lett. 278, 107–114 (1991).
Weber, B. et al. Genomic organization and complete sequence of the human gene encoding the β-subunit of the cGMP phosphodiesterase and its localization to 4p16.3. Nucl. Acids Res. 19, 6263–6268 (1991).
Lipkin, V.M. et al. β-subunit of bovine rod photoreceptor phosphodiesterase. Comparison with the phosphodiesterase family. J. biol. Chem. 265, 12955–12969 (1990).
Bowes, C., Li, T., Danciger, M., Baxter, L.C., Applebury, M.L. & Farber, D.B. Retinal degeneration in the rd mouse is caused by a defect in the β subunit of rod cGMP-phosphodiesterase. Nature 347, 677–680 (1990).
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).
Rosenfeld, P.J., Cowley, G.S., McGee, T.L., Sandberg, M.A., Berson, E.L & Dryja, T.R. A null mutation in the rhodopsin gene causes rod photoreceptor dysfunction and autosomal recessive retinitis pigmentosa. Nature Genet. 1, 209–213 (1992).
McLaughlin, M.E., Ehrhart, T.L., Berson, E.L. & Dryja, T.R. Mutation spectrum of the gene encoding the β subunit of rod phosphodiesterase among patients with autosomal recessive retinitis pigmentosa. Proc. natn. Acad. Sci. U.S.A. 92, 3249–3253 (1995).
Bayes, M. et al. Homozygous tandem duplication within the gene encoding the β-subunit of rod phosphodiesterase as a cause for autosomal recessive retinitis pigmentosa. Hum Mut. 5, 228–234 (1995).
Bloomquist, B.T. et al. Isolation of a putative phospholipase C gene of Drosophila, norpA, and its role in phototransduction. Cell 54, 723–733 (1988).
Meyertholen, E.R., Stein, P.J., Williams, M.A. & Ostroy, S.E. . Studies of the Drosophila norpA phototransduction mutant. II. Photoreceptor degeneration and rhodopsin maintenance. J. comp. Physiol. A 161, 793–798 (1987).
Farber, D.B. & Lolley, R.N. Enzymic basis for cyclic GMP accumulation in degenerative photoreceptor cells of mouse retina. J. eye. nucl. Res. 2, 139–148 (1976).
Farber, D.B. & Lolley, R.N. Cyclic guanosine monophosphate: elevation in degenerating photoreceptor cells of the C3H mouse retina. Science 186, 449–451 (1974).
Aguirre, G., Farber, D., Lolley, R., Fletcher, R.T. & Chader, G.J. Rod-cone dysplasia in Irish setters: a defect in cyclic GMP metabolism in visual cells. Science 201, 1133–1134 (1978).
Suber, M.L. et al. Irish setter dogs affected with rod/cone dysplasia contain a nonsense mutation in the rod cGMP phosphodiesterase B-subunit gene. Proc. natn. Acad. Sci. U.S.A. 90, 3968–3972 (1993).
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, 664–666 (1977).
Ulshafer, R.J., Garcia, C.A. & Hollyfield, J.G. Sensitivity of photoreceptors to elevated levels of cGMP in the human retina. Invest. Ophthamol. Vis. Sci. 19, 1236–1241 (1980).
Chang, G.Q., Hao, Y. & Wong, F. Apoptosis: final common pathway of photoreceptor death in rd, rds, and rhodopsin mutant mice. Neuron 11, 595–605 (1993).
Portera-Cailliau, C., Sung, C.H., Nathans, J. & Adler, R. Apoptotic photoreceptor cell death in mouse models of retinitis pigmentosa. Proc. natn. Acad. Sci. U.S.A 91, 974–978 (1994).
Kunkel, L.M. et al. Analysis of human Y-chromosome-specific reiterated DNA in chromosome variants. Proc. natn. Acad. Sci. U.S.A 74, 1245–1249 (1977).
Reichel, E., Bruce, A.M., Sandberg, M.A. & Berson, E.L. An electroretinographic and molecular genetic study of X-linked cone degeneration. Am. J. Ophthalmol. 108, 540–547 (1989).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Huang, S., Pittler, S., Huang, X. et al. Autosomal recessive retinitis pigmentosa caused by mutations in the α subunit of rod cGMP phosphodiesterase. Nat Genet 11, 468–471 (1995). https://doi.org/10.1038/ng1295-468
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ng1295-468
This article is cited by
-
A novel homozygous missense substitution p.Thr313Ile in the PDE6B gene underlies autosomal recessive retinitis pigmentosa in a consanguineous Pakistani family
BMC Ophthalmology (2023)
-
Novel variants in PDE6A and PDE6B genes and its phenotypes in patients with retinitis pigmentosa in Chinese families
BMC Ophthalmology (2022)
-
A new PDE6A missense variant p.Arg544Gln in rod–cone dystrophy
Documenta Ophthalmologica (2021)
-
Biochemistry and physiology of zebrafish photoreceptors
Pflügers Archiv - European Journal of Physiology (2021)
-
Natural models for retinitis pigmentosa: progressive retinal atrophy in dog breeds
Human Genetics (2019)