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:

Mutations in the gene encoding 11-cis retinol dehydrogenase cause delayed dark adaptation and fundus albipunctatus

Nature Genetics volume 22, pages 188–191 (1999)Cite this article

Abstract

The metabolic pathways that produce 11-cis retinal are important for vision because this retinoid is the chromophore residing in rhodopsin and the cone opsins. The all-trans retinal that is generated after cone and rod photopigments absorb photons of light is recycled back to 11-cis retinal by the retinal pigment epithelium and Müller cells of the retina. Several of the enzymes involved have recently been purified and molecularly cloned1,2,3; here we focus on 11-cis retinol dehydrogenase (encoded by the gene RDH5; chromosome 12q13-14; ref. 4), the first cloned enzyme in this pathway. This microsomal enzyme is abundant in the retinal pigment epithelium5, where it has been proposed to catalyse the conversion of 11-cis retinol to 11-cis retinal. We evaluated patients with hereditary retinal diseases featuring subretinal spots (retinitis punctata albescens and fundus albipunctatus) and patients with typical dominant or recessive retinitis pigmentosa for mutations in RDH5. Mutations were found only in two unrelated patients, both with fundus albipunctatus; they segregated with disease in the respective families. Recombinant mutant 11-cis retinol dehydrogenases had reduced activity compared with recombinant enzyme with wild-type sequence. Our results suggest that mutant alleles in RDH5 are a cause of fundus albipunctatus, a rare form of stationary night blindness characterized by a delay in the regeneration of cone and rod photopigments.

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: Mutations in RDH5 in families of patients 097-002 and 084-001.
Figure 2: Expression of wild-type and mutant enzymes in transfected COS-1 cells and activity measurements by HPLC analysis.
Figure 3: Fundus photos.
Figure 4: Time course of dark adaptation in patient 084-001 at age 15 and a normal control after exposure to a white background bleaching light of 1,713 candela/m2 for 5 min followed by darkness.
Figure 5: Full-field electroretinograms16 (ERGs) of a normal control and patients 097-002 and 084-001.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Simon, A., Hellman, U., Wernstedt, C. & Eriksson, U. The retinal pigment epithelial-specific 11-cis retinol dehydrogenase belongs to the family of short chain alcohol dehydrogenases. J. Biol. Chem. 270, 1107–1112 (1995).

    Article  CAS  Google Scholar 

  2. Haeseleer, F., Huang, J., Lebioda, L., Saari, J.C. & Palczewski, K. Molecular characterization of a novel short-chain dehydrogenase/reductase that reduces all-trans-retinal. J. Biol. Chem. 273, 21790–21799 (1998).

    Article  CAS  Google Scholar 

  3. Ruiz, A. et al. Molecular and biochemical characterization of lecithin retinol acyltransferase. J. Biol. Chem. 274, 3834–3841 (1999).

    Article  CAS  Google Scholar 

  4. Simon, A., Lagercrantz, J., Bajalica-Lagercrantz, S. & Eriksson, U. Primary structure of human 11-cis retinol dehydrogenase and organization and chromosomal localization of the corresponding gene. Genomics 36, 424–430 (1996).

    Article  CAS  Google Scholar 

  5. Simon, A., Romert, A., Gustafsson, A.-L., McCaffrey, J.M. & Eriksson, U. Intracellular localization and membrane topology of 11-cis retinol dehydrogenase in the retinal pigment epithelium suggest a compartmentalized synthesis of 11-cis retinaldehyde. J. Cell Sci. 112, 549–558 (1999).

    CAS  PubMed  Google Scholar 

  6. Wang, J., Chai, X.Y., Eriksson, U. & Napoli, J.L. Activity of human 11-cis retinol dehydrogenase (Rdh5) with steroids and retinoids and expression of its mRNA in extra-ocular human tissue. Biochem. J. 338, 23–27 (1999).

    Article  CAS  Google Scholar 

  7. Carr, R.E., Ripps, H. & Siegel, I.M. Visual pigment kinetics and adaptation in fundus albipunctatus. Doc. Ophthal. Proc. Series 4, 193–204 (1974).

    Article  Google Scholar 

  8. Marmor, M.F. Defining fundus albipunctatus. Doc. Ophthal. Proc. Series 13, 227–233 (1976).

    Google Scholar 

  9. Ripps, H. Night blindness revisited: from man to molecules. Proctor lecture. Invest. Ophthalmol. Vis. Sci. 23, 588–609 (1982).

    CAS  PubMed  Google Scholar 

  10. Morimura, H., Berson, E.L. & Dryja, T.P. Recessive mutations in the gene encoding cellular retinaldehyde-binding protein in a form of retinitis punctata albescens. Invest. Ophthalmol. Vis. Sci. 40, 1000–1004 (1999).

    CAS  PubMed  Google Scholar 

  11. Green, S., Issemann, I. & Sheer, E. A versatile in vivo and in vitro expression vector for protein engineering. Nucleic Acids Res. 16, 369 (1988).

    Article  CAS  Google Scholar 

  12. Kunkel, T.A., Roberts, J.D. & Zakour, R.A. Rapid and efficient site-specific mutagenesis without phenotypic selection. Methods Enzymol. 154, 367–382 (1987).

    Article  CAS  Google Scholar 

  13. Vieira, J. & Messing, J. Production of single-stranded plasmid DNA. Methods Enzymol. 153, 3–11 (1987).

    Article  CAS  Google Scholar 

  14. Romert, A., Tuvendal, P., Simon, A., Dencker, L. & Eriksson, U. The identification of a 9-cis retinol dehydrogenase in the mouse embryo reveals a pathway for synthesis of 9-cis retinoic acid. Proc. Natl Acad. Sci. USA 95, 4404–4409 (1998).

    Article  CAS  Google Scholar 

  15. Berson, E.L., Gouras, P. & Gunkel, R.D. Rod responses in retinitis pigmentosa, dominantly inherited. Arch. Ophthalmol. 80, 58–67 (1968).

    Article  CAS  Google Scholar 

  16. Berson, E.L. Retinitis pigmentosa and allied retinal diseases: electrophysiologic findings. Trans. Am. Acad. Ophthalmol. Otolaryngol. 81, 659–666 (1976).

    Google Scholar 

Download references

Acknowledgements

We thank B. Åkerblom and T. McGee for expert technical assistance; J.-O. Höög for helpful discussions; and U. Bergman and A. Tuuttila for help with the HPLC analyses. This work was supported by grants from the NIH (EY08683, EY00169) and the Foundation Fighting Blindness, and by the Swedish Medical Research Council (K99-03P-12070-03C, U.E.). The cooperative research agreement between the Ludwig Institute for Cancer Research/Stockholm Branch and Fuji Photo Film (Europe) is gratefully acknowledged.

Author information

Author notes

  1. András Simon

    Present address: Department of Biochemistry and Molecular Biology, University College London, Gower Street, WC1E 6BT, London, UK

  2. Hiroyuki Yamamoto and András Simon: These authors contributed equally to this work.

Authors and Affiliations

  1. Berman-Gund Laboratory for the Study of Retinal Degenerations and the Ocular Molecular Genetics Institute, Harvard Medical School, Massachusetts Eye & Ear Infirmary, Boston, Massachusetts, USA

    Hiroyuki Yamamoto, Eddie Harris, Eliot L. Berson & Thaddeus P. Dryja

  2. Ludwig Institute for Cancer Research, Stockholm, Sweden

    András Simon & Ulf Eriksson

Authors
  1. Hiroyuki Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. András Simon
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ulf Eriksson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eddie Harris
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Eliot L. Berson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Thaddeus P. Dryja
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thaddeus P. Dryja.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yamamoto, H., Simon, A., Eriksson, U. et al. Mutations in the gene encoding 11-cis retinol dehydrogenase cause delayed dark adaptation and fundus albipunctatus. Nat Genet 22, 188–191 (1999). https://doi.org/10.1038/9707

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/9707

This article is cited by

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