1 Rhodopsin Mutations in Congenital Night Blindness

  • Suzanne D. McAlear
  • Timothy W. Kraft
  • Alecia K. Gross
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 664)

Abstract

While there are over 100 distinct mutations in the rhodopsin gene that are found in patients with the degenerative disease autosomal dominant retinitis pigmentosa (ADRP), there are only four known mutations in the rhodopsin gene found in patients with the dysfunction congenital stationary night blindness (CSNB). CSNB patients have a much less severe phenotype than those with ADRP; the patients only lose rod function which affects their vision under dim light conditions, whereas their cone function remains relatively unchanged. The known rhodopsin CSNB mutations are found clustered around the site of retinal attachment. Two of the mutations encode replacements of neutral amino acids with negatively charged ones (A292E and G90D), and the remaining two are neutral amino acid replacements (T94I and A295V). All four of these mutations have been shown to constitutively activate the apoprotein in vitro. The mechanisms by which these mutations lead to night blindness are still not known with certainty, and remain the subject of some controversy. The dominant nature of these genetic defects, as well as the relative normalcy of vision in individuals with half the complement of wild type rhodopsin, suggest that it is an active property of the mutant opsin proteins that leads to defective rod vision rather than a loss of some needed function. Herein, we review the known biochemical and electrophysiological data for the four known rhodopsin mutations found in patients with CSNB.

Keywords

Carboxylate Retina Lysine Polypeptide Barium 

Notes

Acknowledgments

The authors thank T.G. Wensel and V.E. Wotring for critical comments on this manuscript. Our research is supported by grants from the EyeSight Foundation of Alabama, the Karl Kirchgessner Foundation, and by NIH grant EY019311.

References

  1. al-Jandal N, Farrar GJ, Kiang A-S et al (1999) A novel mutation within the rhodopsin gene (Thr-94-Ile) causing autosomal dominant congenital stationary night blindness. Hum Mutat 13:75–81CrossRefPubMedGoogle Scholar
  2. Barlow HB (1988) The thermal limit to seeing. Nature 334:296–297CrossRefPubMedGoogle Scholar
  3. Baylor DA, Matthews G, Yau KW (1980) Two components of electrical dark noise in road retinal rod outer segments. J Physiol 309:591–621PubMedGoogle Scholar
  4. Baylor DA, Nunn BJ, Schnapf JL (1984) The photocurrent, noise and spectral sensitivity of rods of the monkey Macaca fascicularis. J Physiol (Lond) 357:575–607Google Scholar
  5. Cornwall MC, Fain GL (1994) Bleaching pigment activates transducin in isolated rods of the salamander retina. J Physiol (Lond) 480:261–279Google Scholar
  6. Dizhoor A, Woodruff M, Olshevskaya E et al (2008) Night blindness and the mechanism of constitutive signaling of mutant G90D rhodopsin. J Neurosci 28:11662–11672CrossRefPubMedGoogle Scholar
  7. Dowling JE (1960) Chemistry of visual adaptation in the rat. Nature 188:114–118CrossRefPubMedGoogle Scholar
  8. Dryja TP, Berson EL, Rao VR et al (1993) Heterozygous missense mutation in the rhodopsin gene as a cause of congenital stationary night blindness. Nat Genet 4:280–283CrossRefPubMedGoogle Scholar
  9. Gal A, Orth U, Baehr W et al (1994) Heterozygous missense mutation in the rod cGMP phosphodiesterase beta-subunit gene in autosomal dominant stationary night blindness. Nat Genet 7:551CrossRefPubMedGoogle Scholar
  10. Gross AK, Rao VR, Oprian DD (2003) Characterization of rhodopsin congenital night blindness mutant T94I. Biochemistry 42:2009–2015CrossRefPubMedGoogle Scholar
  11. Gross AK, Xie G, Oprian DD (2003) Slow binding of retinal to rhodopsin mutants G90D and T94D. Biochemistry 42:2002–2008CrossRefPubMedGoogle Scholar
  12. Jin S, Cornwall MC, Oprian DD (2003) Opsin activation as a cause of congenital night blindness. Nat Neurosci 6:731–735CrossRefPubMedGoogle Scholar
  13. Keen TJ, Inglehearn CF, Lester DH et al (1991) Autosomal dominant retinitis pigmentosa: four new mutations in rhodopsin, one of the in the retinal attachment site. Genomics 11:199–205CrossRefPubMedGoogle Scholar
  14. Krispel CM, Chen D, Melling N et al (2006) RGS expression rate-limits recovery of rod photoresponses. Neuron 51:409–416CrossRefPubMedGoogle Scholar
  15. Krispel CM, Chen CK, Simon MI et al (2003) Novel form of adaptation in mouse retinal rods speeds recovery of phototransduction. J Gen Physiol 122:703–712CrossRefPubMedGoogle Scholar
  16. Lem J, Krasnoperova NV, Calvert PD, et al (1999) Morphological, physiological and biochemical changes in rhodopsin knockout mice. Proc Natl Acad Sci USA 96:736–741CrossRefPubMedGoogle Scholar
  17. Melia TJ, Cowan CW, Angelson JK et al (1997) A comparison of the efficiency of G protein activation by ligand-free and light-activated forms of rhodopsin. Biophys J 73:3182–3191CrossRefPubMedGoogle Scholar
  18. Nakanishi K, Balogh-Nair V, Arnaboldi M et al (1980) An external point-charge model for bacteriorhodopsin to account for its purple color. J Am Chem Soc 102:7945–7947CrossRefGoogle Scholar
  19. Nathans J (1990) Determinants of visual pigment absorbance: identification of the retinylidene Schiff’s base counterion in bovine rhodopsin. Biochemistry 29:9746–9752CrossRefPubMedGoogle Scholar
  20. Ng PC, Henikoff S (2001) Predicting deleterious amino acid substitutions. Genome Res 11:863–874CrossRefPubMedGoogle Scholar
  21. Rao V, Cohen GB, Oprian DD (1994) Rhodopsin mutation G90D and a molecular mechanism for congenital night blindness. Nature 367:639–642CrossRefPubMedGoogle Scholar
  22. Rieke F, Baylor DA (1996) Molecular origin of continuous dark noise in rod photoreceptors. Biophys J 71:2553–2572CrossRefPubMedGoogle Scholar
  23. Robinson PR, Cohen GB, Zhukovsky EA et al (1992) Constitutively active mutants of rhodopsin. Neuron 9:719–725CrossRefPubMedGoogle Scholar
  24. Sakmar TP, Franke RR, Khorana HG (1989) Glutamic acid-113 serves as the retinylidene Schiff base counterion in bovine rhodopsin. Proc Natl Acad Sci USA 86:8309–8313CrossRefPubMedGoogle Scholar
  25. Sieving PA, Fowler ML, Bush RA et al (2001) Constitutive “light” adaptation in rods from G90D rhodopsin: a mechanism for human congenital nightblindness without rod cell loss. J Neurosci 21:5449–5460PubMedGoogle Scholar
  26. Sieving PA, Richards JE, Naarendorp F et al (1995) Dark-light: model for nightblindness from the human rhodopsin Gly-90 –> Asp mutation. Proc Natl Acad Sci 92:880–884CrossRefPubMedGoogle Scholar
  27. Steinberg G, Ottolenghi M, Sheves M (1993) pKa of the protonated Schiff base of bovine rhodopsin: A study with artificial pigments. Biophys J 64:1499–1502CrossRefPubMedGoogle Scholar
  28. Sullivan JM, Scott KM, Falls HF et al (1993) A novel rhodopsin mutation at the retinal binding site (LYS 296 MET) in ADRP. Invest Ophthalmol Vis Sci 34:1149Google Scholar
  29. Szabo V, Kreienkamp H-J, Rosenberg T et al (2007) p.Gln200Glu, a putative constitutively active mutant of rod á-transducin (GNAT1) in autosomal dominant congenital stationary night blindness. Hum Mutat 28:741–742CrossRefPubMedGoogle Scholar
  30. Tam B, Moritz O (2007) Dark rearing rescues P23H rhodopsin-induced retinal degeneration in a transgenic Xenopus laevis model of retinitis pigmentosa: a chromophore-dependent mechanism characterized by production of N-terminally truncated mutant rhodopsin. J Neurosci 27(34):9043–9053CrossRefPubMedGoogle Scholar
  31. Xie G, Gross AK, Oprian DD (2003) An opsin mutant with increased thermal stability. Biochemistry 42:1995–2001CrossRefPubMedGoogle Scholar
  32. Zeitz C, Gross AK, Leifert D et al (2008) Identification and functional characterization of a novel rhodopsin mutation associated with autosomal dominant CSNB. Invest Ophthalmol Visc Sci 49:4105–4114CrossRefGoogle Scholar
  33. Zhukovsky EA, Robinson PR, Oprian DD (1992) Changing the location of the Schiff base counterion in rhodopsin. Biochemistry 31:10400–10405CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Suzanne D. McAlear
    • 1
  • Timothy W. Kraft
    • 1
  • Alecia K. Gross
    • 1
  1. 1.University of Alabama at BirminghamBirminghamUSA

Personalised recommendations