Abstract
D190N, a missense mutation in rhodopsin, causes photoreceptor degeneration in patients with autosomal dominant retinitis pigmentosa (adRP). Two competing hypotheses have been developed to explain why D190N rod photoreceptors degenerate: (a) defective rhodopsin trafficking prevents proteins from correctly exiting the endoplasmic reticulum, leading to their accumulation, with deleterious effects or (b) elevated mutant rhodopsin expression and unabated signaling causes excitotoxicity. A knock-in D190N mouse model was engineered to delineate the mechanism of pathogenesis. Wild type (wt) and mutant rhodopsin appeared correctly localized in rod outer segments of D190N heterozygotes. Moreover, the rhodopsin glycosylation state in the mutants appeared similar to that in wt mice. Thus, it seems plausible that the injurious effect of the heterozygous mutation is not related to mistrafficking of the protein, but rather from constitutive rhodopsin activity and a greater propensity for chromophore isomerization even in the absence of light.
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References
Boughman JA, Conneally PM, Nance WE (1980) Population genetic studies of retinitis pigmentosa. Am J Hum Genet 32:223–235
Berson EL (1993) Retinitis pigmentosa: the friedenwald lecture. Invest Opthal Vis Sci 34:1655–1676
Hartong DT, Berson EL, Dryja TP (2006) Retinitis pigmentosa. Lancet 368:1795–1809
Rivolta C, Sharon D, De Angelis MM, Dryja TP (2002) Retinitis pigmentosa and allied diseases: numerous diseases, genes, and inheritance patterns. Hum Mol Genet 11:1219–1227
Wilson JH, Wensel TG (2003) The nature of dominant mutations of rhodopsin and implications for gene therapy. Mol Neurobiol 28:149–158
Dryja TP, Hahn LB, Cowley GS, McGee TL, Berson EL (1991) Mutation spectrum of the rhodopsin gene among patients with autosomal dominant retinitis pigmentosa. Proc Natl Acad Sci USA 88:9370–9374
Filipek S, Stenkamp RE, Teller DC, Palczewski K (2003) G protein-coupled receptor rhodopsin: a prospectus. Annu Rev Physiol 65:851–879
Jager S, Palczewski K, Hofmann KP (1996) Opsin/all-trans-retinal complex activates transducin by different mechanisms than photolyzed rhodopsin. Biochemistry 35:2901–2908
Palczewski K (2006) G protein-coupled receptor rhodopsin. Annu Rev Biochem 75:743–767
Palczewski K, Kumasaka T, Hori T, Behnke CA, Motoshima H, Fox BA, Le Trong I, Teller DC, Okada T, Stenkamp RE, Yamamoto M, Miyano M (2000) Crystal structure of rhodopsin: a G protein-coupled receptor. Science 289:739–745
Smith SO (2010) Structure and activation of the visual pigment rhodopsin. Annu Rev Biophys 39:309–328
Burns ME, Arshavsky VY (2005) Beyond counting photons: trials and trends in vertebrate visual transduction. Neuron 48:387–401
Tsui I, Chou CL, Palmer N, Lin CS, Tsang SH (2008) Phenotype-genotype correlations in autosomal dominant retinitis pigmentosa caused by RHO, D190N. Curr Eye Res 33:1014–1022
Park SP, Lee W, Bae EJ, Greenstein V, Sin BH, Chang S, Tsang SH (2014) Early structural anomalies observed by high-resolution imaging in two related cases of autosomal-dominant retinitis pigmentosa. Ophthalmic Surg Lasers Imaging Retina 45:469–473
Tsai YT, Wu WH, Lee TT, Wu WP, Xu CL, Park KS, Cui X, Justus S, Lin CS, Jauregui R, Su PY, Tsang SH (2018) Clustered regularly interspaced short palindromic repeats-based genome surgery for the treatment of autosomal dominant retinitis pigmentosa. Ophthalmology 125:1421–1430
Kaushal S, Khorana HG (1994) Structure and function in rhodopsin. 7. Point mutations associated with autosomal dominant retinitis pigmentosa. Biochemistry 33:6121–6128
Janz JM, Fay JF, Farrens DL (2003) Stability of dark state rhodopsin is mediated by a conserved ion pair in intradiscal loop E-2. J Biol Chem 278:16982–16991
Yan EC, Kazmi MA, Ganim Z, Hou JM, Pan D, Chang BS, Sakmar TP, Mathies RA (2003) Retinal counterion switch in the photoactivation of the G protein-coupled receptor rhodopsin. Proc Natl Acad Sci USA 100:9262–9267
Liu MY, Liu J, Mehrotra D, Liu Y, Guo Y, Baldera-Aguayo PA, Mooney VL, Nour AM, Yan EC (2013) Thermal stability of rhodopsin and progression of retinitis pigmentosa: comparison of S186W and D190N rhodopsin mutants. J Biol Chem 288:17698–17712
Sancho-Pelluz J, Tosi J, Hsu CW, Lee F, Wolpert K, Tabacaru MR, Greenberg JP, Tsang SH, Lin CS (2012) Mice with a D190N mutation in the gene encoding rhodopsin: a model for human autosomal-dominant retinitis pigmentosa. Mol Med 18:549–555
Sakami S, Maeda T, Bereta G, Okano K, Golczak M, Sumaroka A, Roman AJ, Cideciyan AV, Jacobson SG, Palczewski K (2011) Probing mechanisms of photoreceptor degeneration in a new mouse model of the common form of autosomal dominant retinitis pigmentosa due to P23H opsin mutations. J Biol Chem 286:10551–10567
Zencak D, Schouwey K, Chen D, Ekström P, Tanger E, Bremner R, van Lohuizen M, Arsenijevic Y (2013) Retinal degeneration depends on Bmi1 function and reactivation of cell cycle proteins. Proc Natl Acad Sci USA 110:593–601
Fain GL, Lisman JE (1993) Photoreceptor degeneration in vitamin A deprivation and retinitis pigmentosa: the equivalent light hypothesis. Exp Eye Res 57:335–340
Fain GL, Lisman JE (1999) Light, Ca2+, and photoreceptor death: new evidence for the equivalent-light hypothesis from arrestin knockout mice. Invest Ophthalmol Vis Sci 40:2770–2772
Lisman J, Fain G (1995) Support for the equivalent light hypothesis for RP. Nat Med 1:1254–1255
Baylor DA, Nunn BJ, Schnapf JL (1984) The photocurrent, noise and spectral sensitivity of rods of the monkey Macaca fascicularis. J Physiol 357:575–607
Acknowledgements
We greatly appreciate the assistance of the members of the Bernard & Shirlee Brown Glaucoma laboratory, especially to Chun-Wei Hsu for technical support. SHT is a Burroughs-Wellcome Program in Biomedical Sciences Fellow, and is also supported by the Charles E. Culpeper-Partnership for Cures 07-CS3, Crowley Research Fund, Schneeweiss Stem Cell Fund, New York State N09G-302, Foundation Fighting Blindness [TA-NMT-0116-0692-COLU] (Owings Mills, MD), TS080017 from US Department of Defense, NIH Grants [P30EY019007, R01EY018213, R01EY024698, R01EY026682, R21AG050437], Research to Prevent Blindness (New York, NY), and Joel Hoffmann Scholarship. CSL is the Homer McK. Rees Scholar. JSP is a BEST2016 awardee (BEST/2016/030, Conselleria de Educación, Investigación, Cultura y Deporte; Generalitat Valenciana) and his research is supported by a Prometeo Grant (PROMETEO/2016/094; Conselleria de Educación, Investigación, Cultura y Deporte; Generalitat Valenciana) and by internal funds from Universidad Católica de Valencia San Vicente Mártir (2018-128-001). VBM is supported by NIH Grants K08EY020530, R01EY016822, The Doris Duke Charitable Foundation Grant #2013103, and Research to Prevent Blindness (New York, NY); GV is supported by NIH Grants [F30EYE027986 and T32GM007337].
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JSP and XC ran most of the experiments: the histology, immunostainings, electron microscopy, ERGs, and glycosilation; WL helped with glycosylation experiments; YT, WS, SK, and CH ran part of the ERG recordings and the western blotting; IW assisted and advised with the experiments; GV, AGB, and VBM created the modeling for D190N rhodopsin and prepared Fig. 1; CSL created the animal model; SHT planned and supervised the experiments; JSP, SJ, and KSP wrote the main document; all authors reviewed the manuscript.
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Sancho-Pelluz, J., Cui, X., Lee, W. et al. Mechanisms of neurodegeneration in a preclinical autosomal dominant retinitis pigmentosa knock-in model with a RhoD190N mutation. Cell. Mol. Life Sci. 76, 3657–3665 (2019). https://doi.org/10.1007/s00018-019-03090-9
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DOI: https://doi.org/10.1007/s00018-019-03090-9