Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Defects in RGS9 or its anchor protein R9AP in patients with slow photoreceptor deactivation

Nature volume 427, pages 75–78 (2004)Cite this article

Abstract

The RGS proteins are GTPase activating proteins that accelerate the deactivation of G proteins in a variety of signalling pathways in eukaryotes1,2,3,4,5,6. RGS9 deactivates the G proteins (transducins) in the rod and cone phototransduction cascades7,8. It is anchored to photoreceptor membranes by the transmembrane protein R9AP (RGS9 anchor protein), which enhances RGS9 activity up to 70-fold9,10,11. If RGS9 is absent or unable to interact with R9AP, there is a substantial delay in the recovery from light responses in mice4,12,13. We identified five unrelated patients with recessive mutations in the genes encoding either RGS9 or R9AP who reported difficulty adapting to sudden changes in luminance levels mediated by cones. Standard visual acuity was normal to moderately subnormal, but the ability to see moving objects, especially with low-contrast, was severely reduced despite full visual fields; we have termed this condition bradyopsia. To our knowledge, these patients represent the first identified humans with a phenotype associated with reduced RGS activity in any organ.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: W299 in the RGS9 catalytic domain.
Figure 2: Dynamic acuity.
Figure 3: Full-field ERGs.
Figure 4: Double-flash ERGs.

Similar content being viewed by others

References

  1. Dohlman, H. G., Song, J., Ma, D., Courchesne, W. E. & Thorner, J. Sst2, a negative regulator of pheromone signaling in the yeast Saccharomyces cerevisiae: Expression, localization, and genetic interaction and physical association with Gpa1 (the G-protein α subunit). Mol. Cell. Biol. 16, 5194–5209 (1996)

    Article  CAS  Google Scholar 

  2. Rogers, J. H. et al. RGS4 causes increased mortality and reduced cardiac hypertrophy in response to pressure overload. J. Clin. Invest. 104, 567–576 (1999)

    Article  CAS  Google Scholar 

  3. Oliveira-dos-Santos, A. J. et al. Regulation of T cell activation, anxiety, and male aggression by RGS2. Proc. Natl Acad. Sci. USA 97, 12272–12277 (2000)

    Article  ADS  CAS  Google Scholar 

  4. Chen, C. K. et al. Slowed recovery of rod photoresponse in mice lacking the GTPase accelerating protein RGS9-1. Nature 403, 557–560 (2000)

    Article  ADS  CAS  Google Scholar 

  5. Sinnarajah, S. et al. RGS2 regulates signal transduction in olfactory neurons by attenuating activation of adenylyl cyclase III. Nature 409, 1051–1055 (2001)

    Article  ADS  CAS  Google Scholar 

  6. Heximer, S. P. et al. Hypertension and prolonged vasoconstrictor signaling in RGS2-deficient mice. J. Clin. Invest. 111, 445–452 (2003)

    Article  CAS  Google Scholar 

  7. He, W., Cowan, C. W. & Wensel, T. G. RGS9, a GTPase accelerator for phototransduction. Neuron 20, 95–102 (1998)

    Article  Google Scholar 

  8. Cowan, C. W., Fariss, R. N., Sokal, I., Palczewski, K. & Wensel, T. G. High expression levels in cones of RGS9, the predominant GTPase accelerating protein of rods. Proc. Natl Acad. Sci. USA 95, 5351–5356 (1998)

    Article  ADS  CAS  Google Scholar 

  9. Hu, G. & Wensel, T. G. R9AP, a membrane anchor for the photoreceptor GTPase accelerating protein, RGS9-1. Proc. Natl Acad. Sci. USA 99, 9755–9760 (2002)

    Article  ADS  CAS  Google Scholar 

  10. Lishko, P. V., Martemyanov, K. A., Hopp, J. A. & Arshavsky, V. Y. Specific binding of RGS9-Gβ 5L to protein anchor in photoreceptor membranes greatly enhances its catalytic activity. J. Biol. Chem. 277, 24376–24381 (2002)

    Article  CAS  Google Scholar 

  11. Hu, G., Zhang, Z. & Wensel, T. G. Activation of RGS9-1 GTPase acceleration by its membrane anchor, R9AP. J. Biol. Chem. 278, 14550–14554 (2003)

    Article  CAS  Google Scholar 

  12. Lyubarsky, A. L. et al. RGS9-1 is required for normal inactivation of mouse cone phototransduction. Mol. Vis. 7, 71–78 (2001)

    CAS  PubMed  Google Scholar 

  13. Martemyanov, K. A. et al. The DEP domain determines subcellular targeting of the GTPase activating protein RGS9 in vivo. J. Neurosci. 23, 10175–10181 (2003)

    Article  CAS  Google Scholar 

  14. Zhang, K. et al. Structure, alternative splicing, and expression of the human RGS9 gene. Gene 240, 23–34 (1999)

    Article  CAS  Google Scholar 

  15. Rahman, Z. et al. Cloning and characterization of RGS9-2: A striatal-enriched alternatively spliced product of the RGS9 gene. J Neurosci. 19, 2016–2026 (1999)

    Article  CAS  Google Scholar 

  16. Kooijman, A. C., Houtman, A., Damhof, A. & van Engelen, J. P. Prolonged electro-retinal response suppression (PERRS) in patients with stationary subnormal visual acuity and photophobia. Doc. Ophthalmol. 78, 245–254 (1991)

    Article  CAS  Google Scholar 

  17. Slep, K. C. et al. Structural determinants for regulation of phosphodiesterase by a G protein at 2.0 Å. Nature 409, 1071–1077 (2001)

    Article  ADS  CAS  Google Scholar 

  18. Sandberg, M. A., Pawlyk, B. S. & Berson, E. L. Acuity recovery and cone pigment regeneration after a bleach in patients with retinitis pigmentosa and rhodopsin mutations. Invest. Ophthalmol. Vis. Sci. 40, 2457–2461 (1999)

    CAS  PubMed  Google Scholar 

  19. Berson, E. L., Gouras, P. & Gunkel, R. D. Progressive cone degeneration, dominantly inherited. Arch. Ophthalmol. 80, 77–83 (1968)

    Article  CAS  Google Scholar 

  20. Kooijman, A. C. et al. Spectral sensitivity function of the a-wave of the human electroretinogram in the dark-adapted eye. Clin. Vision Sci. 6, 379–383 (1991)

    Google Scholar 

  21. Sandberg, M. A. et al. Rod and cone function in the Nougaret form of stationary night blindness. Arch. Ophthalmol. 116, 867–872 (1998)

    Article  CAS  Google Scholar 

  22. Martemyanov, K. A. & Arshavsky, V. Y. Noncatalytic domains of RGS9-1·Gβ5L play a decisive role in establishing its substrate specificity. J. Biol. Chem. 277, 32843–32848 (2002)

    Article  CAS  Google Scholar 

  23. He, W. et al. Modules in the photoreceptor RGS9-1·Gβ5L GTPase-accelerating protein complex control effector coupling, GTPase acceleration, protein folding, and stability. J. Biol. Chem. 275, 37093–37100 (2000)

    Article  CAS  Google Scholar 

  24. Berson, E. L., Gouras, P. & Gunkel, R. D. Rod responses in retinitis pigmentosa, dominantly inherited. Arch. Ophthalmol. 80, 58–66 (1968)

    Article  CAS  Google Scholar 

  25. Andreasson, S. O., Sandberg, M. A. & Berson, E. L. Narrow-band filtering for monitoring low-amplitude cone electroretinograms in retinitis pigmentosa. Am. J. Ophthalmol. 105, 500–503 (1988)

    Article  CAS  Google Scholar 

  26. Marmor, M. F. An international standard for electroretinography. Doc. Ophthalmol. 73, 299–302 (1989)

    Article  CAS  Google Scholar 

  27. Marmor, M. F. & Zrenner, E. Standard for clinical electroretinography (1994 update). Doc. Ophthalmol. 89, 199–210 (1995)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank T. Li, T. McGee and B. Pawlyk for assistance. This study followed the tenets of the Declaration of Helsinki; it was approved by the Human Studies Committees of the authors' institutions and all patients gave their consent before their participation. This work was supported by the NIH, the Foundation Fighting Blindness, Owings Mills, Maryland, and the American Heart Association.

Author information

Author notes

  1. Stephanie A. Hagstrom

    Present address: Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio, 44195, USA

Authors and Affiliations

  1. Ocular Molecular Genetics Institute, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, 02114, USA

    Koji M. Nishiguchi, Stephanie A. Hagstrom & Thaddeus P. Dryja

  2. Berman-Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, 02114, USA

    Michael A. Sandberg & Eliot L. Berson

  3. Howe Laboratory of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, 02114, USA

    Kirill A. Martemyanov & Vadim Y. Arshavsky

  4. Department of Ophthalmology, University Hospital Groningen, Groningen, 9700 RB, The Netherlands

    Aart C. Kooijman & Jan W. R. Pott

Authors
  1. Koji M. Nishiguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael A. Sandberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Aart C. Kooijman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kirill A. Martemyanov
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jan W. R. Pott
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Stephanie A. Hagstrom
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Vadim Y. Arshavsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Eliot L. Berson
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Thaddeus P. Dryja
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thaddeus P. Dryja.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

41586_2004_BFnature02170_MOESM1_ESM.pdf

Supplementary Figures: Schematic pedigrees and DNA sequence of selected families with RGS9 and R9AP mutations. (PDF 119 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nishiguchi, K., Sandberg, M., Kooijman, A. et al. Defects in RGS9 or its anchor protein R9AP in patients with slow photoreceptor deactivation. Nature 427, 75–78 (2004). https://doi.org/10.1038/nature02170

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature02170

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing