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Proc Natl Acad Sci U S A. Mar 28, 1995; 92(7): 3070–3074.
PMCID: PMC42361

Defective intracellular transport is the molecular basis of rhodopsin-dependent dominant retinal degeneration.

Abstract

Retinitis pigmentosa (RP) is a group of hereditary human diseases that cause retinal degeneration and lead to eventual blindness. More than 25% of all RP cases in humans appear to be caused by dominant mutations in the gene encoding the visual pigment rhodopsin. The mechanism by which the mutant rhodopsin proteins cause dominant retinal degeneration is still unclear. Interestingly, the great majority of these mutants appear to produce misfolded rhodopsin. We now report the isolation and characterization of 13 rhodopsin mutations that act dominantly to cause retinal degeneration in Drosophila; four of these correspond to identical substitutions in human autosomal dominant RP patients. We demonstrate that retinal degeneration results from interference in the maturation of wild-type rhodopsin by the mutant proteins.

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  • Berson EL. Retinitis pigmentosa. The Friedenwald Lecture. Invest Ophthalmol Vis Sci. 1993 Apr;34(5):1659–1676. [PubMed]
  • Dryja TP. Doyne Lecture. Rhodopsin and autosomal dominant retinitis pigmentosa. Eye (Lond) 1992;6(Pt 1):1–10. [PubMed]
  • Dryja TP, McGee TL, Reichel E, Hahn LB, Cowley GS, Yandell DW, Sandberg MA, Berson EL. A point mutation of the rhodopsin gene in one form of retinitis pigmentosa. Nature. 1990 Jan 25;343(6256):364–366. [PubMed]
  • Dryja TP, Hahn LB, Cowley GS, McGee TL, Berson EL. Mutation spectrum of the rhodopsin gene among patients with autosomal dominant retinitis pigmentosa. Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):9370–9374. [PMC free article] [PubMed]
  • Nathans J, Merbs SL, Sung CH, Weitz CJ, Wang Y. Molecular genetics of human visual pigments. Annu Rev Genet. 1992;26:403–424. [PubMed]
  • Sung CH, Davenport CM, Hennessey JC, Maumenee IH, Jacobson SG, Heckenlively JR, Nowakowski R, Fishman G, Gouras P, Nathans J. Rhodopsin mutations in autosomal dominant retinitis pigmentosa. Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6481–6485. [PMC free article] [PubMed]
  • Bird AC. Investigation of disease mechanisms in retinitis pigmentosa. Ophthalmic Paediatr Genet. 1992 Jun;13(2):57–66. [PubMed]
  • Nathans J. In the eye of the beholder: visual pigments and inherited variation in human vision. Cell. 1994 Aug 12;78(3):357–360. [PubMed]
  • Olsson JE, Gordon JW, Pawlyk BS, Roof D, Hayes A, Molday RS, Mukai S, Cowley GS, Berson EL, Dryja TP. Transgenic mice with a rhodopsin mutation (Pro23His): a mouse model of autosomal dominant retinitis pigmentosa. Neuron. 1992 Nov;9(5):815–830. [PubMed]
  • Robinson PR, Cohen GB, Zhukovsky EA, Oprian DD. Constitutively active mutants of rhodopsin. Neuron. 1992 Oct;9(4):719–725. [PubMed]
  • Dolph PJ, Ranganathan R, Colley NJ, Hardy RW, Socolich M, Zuker CS. Arrestin function in inactivation of G protein-coupled receptor rhodopsin in vivo. Science. 1993 Jun 25;260(5116):1910–1916. [PubMed]
  • Govardhan CP, Oprian DD. Active site-directed inactivation of constitutively active mutants of rhodopsin. J Biol Chem. 1994 Mar 4;269(9):6524–6527. [PubMed]
  • Robinson PR, Buczyłko J, Ohguro H, Palczewski K. Opsins with mutations at the site of chromophore attachment constitutively activate transducin but are not phosphorylated by rhodopsin kinase. Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5411–5415. [PMC free article] [PubMed]
  • Doi T, Molday RS, Khorana HG. Role of the intradiscal domain in rhodopsin assembly and function. Proc Natl Acad Sci U S A. 1990 Jul;87(13):4991–4995. [PMC free article] [PubMed]
  • Sung CH, Schneider BG, Agarwal N, Papermaster DS, Nathans J. Functional heterogeneity of mutant rhodopsins responsible for autosomal dominant retinitis pigmentosa. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8840–8844. [PMC free article] [PubMed]
  • Zuker CS. Phototransduction in Drosophila: a paradigm for the genetic dissection of sensory transduction cascades. Curr Opin Neurobiol. 1992 Oct;2(5):622–627. [PubMed]
  • Sung CH, Davenport CM, Nathans J. Rhodopsin mutations responsible for autosomal dominant retinitis pigmentosa. Clustering of functional classes along the polypeptide chain. J Biol Chem. 1993 Dec 15;268(35):26645–26649. [PubMed]
  • Naash MI, Hollyfield JG, al-Ubaidi MR, Baehr W. Simulation of human autosomal dominant retinitis pigmentosa in transgenic mice expressing a mutated murine opsin gene. Proc Natl Acad Sci U S A. 1993 Jun 15;90(12):5499–5503. [PMC free article] [PubMed]
  • Chang GQ, Hao Y, Wong F. Apoptosis: final common pathway of photoreceptor death in rd, rds, and rhodopsin mutant mice. Neuron. 1993 Oct;11(4):595–605. [PubMed]
  • Huang PC, Gaitan AE, Hao Y, Petters RM, Wong F. Cellular interactions implicated in the mechanism of photoreceptor degeneration in transgenic mice expressing a mutant rhodopsin gene. Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8484–8488. [PMC free article] [PubMed]
  • Sung CH, Makino C, Baylor D, Nathans J. A rhodopsin gene mutation responsible for autosomal dominant retinitis pigmentosa results in a protein that is defective in localization to the photoreceptor outer segment. J Neurosci. 1994 Oct;14(10):5818–5833. [PubMed]
  • Smith DP, Stamnes MA, Zuker CS. Signal transduction in the visual system of Drosophila. Annu Rev Cell Biol. 1991;7:161–190. [PubMed]
  • Zipursky SL, Rubin GM. Determination of neuronal cell fate: lessons from the R7 neuron of Drosophila. Annu Rev Neurosci. 1994;17:373–397. [PubMed]
  • Colley NJ, Baker EK, Stamnes MA, Zuker CS. The cyclophilin homolog ninaA is required in the secretory pathway. Cell. 1991 Oct 18;67(2):255–263. [PubMed]
  • Zuker CS, Cowman AF, Rubin GM. Isolation and structure of a rhodopsin gene from D. melanogaster. Cell. 1985 Apr;40(4):851–858. [PubMed]
  • Stamnes MA, Rutherford SL, Zuker CS. Cyclophilins: a new family of proteins involved in intracellular folding. Trends Cell Biol. 1992 Sep;2(9):272–276. [PubMed]
  • Ondek B, Hardy RW, Baker EK, Stamnes MA, Shieh BH, Zuker CS. Genetic dissection of cyclophilin function. Saturation mutagenesis of the Drosophila cyclophilin homolog ninaA. J Biol Chem. 1992 Aug 15;267(23):16460–16466. [PubMed]
  • Baker EK, Colley NJ, Zuker CS. The cyclophilin homolog NinaA functions as a chaperone, forming a stable complex in vivo with its protein target rhodopsin. EMBO J. 1994 Oct 17;13(20):4886–4895. [PMC free article] [PubMed]
  • Franceschini N, Kirschfeld K. Les phénoménes de pseudopupille dans l'oeil compose de Drosophila. Kybernetik. 1971 Nov;9(5):159–182. [PubMed]
  • Hotta Y, Benzer S. Abnormal electroretinograms in visual mutants of Drosophila. Nature. 1969 Apr 26;222(5191):354–356. [PubMed]
  • MacKenzie D, Arendt A, Hargrave P, McDowell JH, Molday RS. Localization of binding sites for carboxyl terminal specific anti-rhodopsin monoclonal antibodies using synthetic peptides. Biochemistry. 1984 Dec 18;23(26):6544–6549. [PubMed]
  • Oprian DD, Molday RS, Kaufman RJ, Khorana HG. Expression of a synthetic bovine rhodopsin gene in monkey kidney cells. Proc Natl Acad Sci U S A. 1987 Dec;84(24):8874–8878. [PMC free article] [PubMed]
  • Smith DP, Ranganathan R, Hardy RW, Marx J, Tsuchida T, Zuker CS. Photoreceptor deactivation and retinal degeneration mediated by a photoreceptor-specific protein kinase C. Science. 1991 Dec 6;254(5037):1478–1484. [PubMed]
  • Shieh BH, Stamnes MA, Seavello S, Harris GL, Zuker CS. The ninaA gene required for visual transduction in Drosophila encodes a homologue of cyclosporin A-binding protein. Nature. 1989 Mar 2;338(6210):67–70. [PubMed]
  • Britt SG, Feiler R, Kirschfeld K, Zuker CS. Spectral tuning of rhodopsin and metarhodopsin in vivo. Neuron. 1993 Jul;11(1):29–39. [PubMed]
  • Bloomquist BT, Shortridge RD, Schneuwly S, Perdew M, Montell C, Steller H, Rubin G, Pak WL. Isolation of a putative phospholipase C gene of Drosophila, norpA, and its role in phototransduction. Cell. 1988 Aug 26;54(5):723–733. [PubMed]

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