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:

Mutation of a nuclear receptor gene, NR2E3, causes enhanced S cone syndrome, a disorder of retinal cell fate

Abstract

Hereditary human retinal degenerative diseases usually affect the mature photoreceptor topography by reducing the number of cells through apoptosis, resulting in loss of visual function1. Only one inherited retinal disease, the enhanced S-cone syndrome (ESCS), manifests a gain in function of photoreceptors. ESCS is an autosomal recessive retinopathy in which patients have an increased sensitivity to blue light; perception of blue light is mediated by what is normally the least populous cone photoreceptor subtype, the S (short wavelength, blue) cones2,3,4,5,6,7,8. People with ESCS also suffer visual loss, with night blindness occurring from early in life, varying degrees of L (long, red)- and M (middle, green)-cone vision, and retinal degeneration. The altered ratio of S- to L/M-cone photoreceptor sensitivity in ESCS may be due to abnormal cone cell fate determination during retinal development7. In 94% of a cohort of ESCS probands we found mutations in NR2E3 (also known as PNR), which encodes a retinal nuclear receptor recently discovered to be a ligand-dependent transcription factor9. Expression of NR2E3 was limited to the outer nuclear layer of the human retina. Our results suggest that NR2E3 has a role in determining photoreceptor phenotype during human retinogenesis.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Phenotype of ESCS.
Figure 2: Chromatograms showing 11 of 12 mutations identified in ESCS probands.
Figure 3: Pedigrees of consanguineous kindreds with ESCS.
Figure 4: BLAST homology results depicting the protein similarity of human NR2E3 with other receptors in humans as well as other species: human NR2E3 (humNR2E3);
Figure 5: NR2E3 expression

Similar content being viewed by others

References

  1. Rattner, A., Sun, H. & Nathans, J. Molecular genetics of human retinal disease. Annu. Rev. Genet. 33, 89–131 (1999).

    Article  CAS  Google Scholar 

  2. Jacobson, S.G., Marmor, M.F., Kemp, C.M. & Knighton, R.W. SWS (blue) cone hypersensitivity in a newly identified retinal degeneration. Invest. Ophthalmol. Vis. Sci. 31, 827– 838 (1990).

    CAS  PubMed  Google Scholar 

  3. Marmor, M.F., Jacobson, S.G., Foerster, M.H., Kellner, U. & Weleber, R.G. Diagnostic clinical findings of a new syndrome with night blindness, maculopathy, and enhanced S cone sensitivity. Am. J. Ophthalmol. 110, 124– 134 (1990).

    Article  CAS  Google Scholar 

  4. Román, A.J. & Jacobson, S.G. S cone-driven but not S cone-type electroretinograms in the enhanced S cone syndrome. Exp. Eye Res. 53, 685–690 (1991).

    Article  Google Scholar 

  5. Jacobson, S.G., Román, A.J., Román, M.I., Gass, J.D.M. & Parker, J.A. Relatively enhanced S cone function in the Goldmann-Favre Syndrome. Am. J. Ophthalmol. 111, 446–453 (1991).

    Article  CAS  Google Scholar 

  6. Kellner, U., Zrenner, E., Sadowski, B. & Foerster, M.H. Enhanced S cone sensitivity syndrome: long-term follow-up, electrophysiological and psychophysical findings. Clin. Vision Sci. 8, 425–434 (1993).

    Google Scholar 

  7. Hood, D.C., Cideciyan, A.V., Roman, A.J. & Jacobson, S.G. Enhanced S cone syndrome: evidence for an abnormally large number of S cones. Vision Res. 35, 1473–1481 (1995).

    Article  CAS  Google Scholar 

  8. Greenstein, V.C. et al. The enhanced S cone syndrome: an analysis of receptoral and post-receptoral changes. Vision Res. 36, 3711–3722 (1996).

    Article  CAS  Google Scholar 

  9. Kobayashi, M. et al. Identification of a photoreceptor cell-specific nuclear receptor. Proc. Natl Acad. Sci. USA 96, 4814– 4819 (1999).

    Article  CAS  Google Scholar 

  10. Favre, M. A propos de deux cas de degenerescence hyaloideoretinienne. Ophthalmologica 135, 604–609 ( 1958).

    Article  CAS  Google Scholar 

  11. Fishman, G.A., Jampol, L.M. & Goldberg, M.F. Diagnostic features of the Favre-Goldmann syndrome. Br. J. Ophthalmol. 60, 345– 353 (1976).

    Article  CAS  Google Scholar 

  12. Fishman, G.A. & Peachey, N. Rod-cone dystrophy associated with a rod system electroretinogram obtained under photopic conditions. Ophthalmology 96, 913–918 (1989).

    Article  CAS  Google Scholar 

  13. Carmi, R., Elbedour, K., Stone, E.M. & Sheffield V.C. Phenotypic differences among patients with Bardet Biedl syndrome linked to three different loci. Am. J. Med. Genet . 59, 199–203 (1995).

    Article  CAS  Google Scholar 

  14. Willy, P.J. & Mangelsdorf, D.J. Nuclear orphan receptors: the search for novel ligands and signaling pathways. Horm. Signaling 1, 307–358 ( 1998).

    Article  CAS  Google Scholar 

  15. Blumberg, B. & Evans, R.M. Orphan nuclear receptors-new ligands and new possibilities. Genes Dev. 12, 3149 –3155 (1998).

    Article  CAS  Google Scholar 

  16. Wikler, K.C. & Rakic, P. An array of early differentiating cones precedes the emergence of the photoreceptor mosaic in the fetal monkey retina. Proc. Natl Acad. Sci. USA 91, 6534 –6538 (1994).

    Article  CAS  Google Scholar 

  17. Wikler, K.C. & Rakic, P. Development of photoreceptor mosaics in primate retina. Perspect. Dev. Neurobiol. 30, 161–175 (1996).

    Google Scholar 

  18. Hendrickson, A., Bumsted, K. & Dorn, E. The development of photoreceptor-specific proteins in primate retina. 42–45 (Great Basin Visual Science Symposium, University of Utah, Salt Lake City, 1996).

  19. Szél, A., van Veen, T. & Rohlich, P. Retinal cone differentiation. Nature 370, 336 (1994).

    Article  Google Scholar 

  20. Szél, A. et al. Reversed ratio of color-specific cones in rabbit retinal cell transplants. Brain Res. Dev. Brain Res. 81, 1–9 (1994).

    Article  Google Scholar 

  21. Daniel, A., Dumstrei, K., Lengyel, J.A. & Hartenstein, V. The control of cell fate in the embryonic visual system by atonal, tailless and EGFR signaling. Development 126, 2945 –2954 (1999).

    CAS  PubMed  Google Scholar 

  22. Chen, F. et al. Retina-specific nuclear receptor: a potential regulator of cellular retinaldehyde-binding protein expressed in retinal pigment epithelium and Muller glial cells. Proc. Natl Acad. Sci. USA 96, 15149–15154 (1999).

    Article  CAS  Google Scholar 

  23. Adler, R. Determination of cellular types in the retina. Invest. Ophthalmol. Vis. Sci. 34, 1677–1682 (1993).

    CAS  PubMed  Google Scholar 

  24. Cepko, C.L. Retinal cell fate determination. Prog. Retinal Res. 12, 1–12 (1993).

    Article  Google Scholar 

  25. Bumsted, K. & Hendrickson, A. Distribution and development of short-wavelength cones differ between Macaca monkey and human fovea. J. Comp. Neurol. 403, 502– 516 (1999).

    Article  CAS  Google Scholar 

  26. Freund, C., Horsford, D.J. & McInnes, R.R. Transcription factor genes and the developing eye: a genetic perspective. Hum. Mol. Genet. 5, 1471–1488 (1996).

    Article  CAS  Google Scholar 

  27. Cepko, C.L. The roles of intrinsic and extrinsic cues and bHLH genes in the determination of retinal cell fates. Curr. Opin. Neurobiol. 9, 37–46 (1999).

    Article  CAS  Google Scholar 

  28. Jacobson, S.G. et al. Retinal degenerations with truncation mutations in the cone-rod homeobox (CRX) gene. Invest. Ophthalmol. Vis. Sci. 39, 2417–2426 (1998).

    CAS  PubMed  Google Scholar 

  29. Bassam, B.J., Cactano-Anolles, G. & Gresshoff, P.M. > Fast and sensitive silver staining of DNA in polyacrylamide gels. Anal. Biochem. 196, 80– 83 (1991).

    Article  CAS  Google Scholar 

  30. Swiderski, R.E. et al. Expression pattern and in situ localization of the mouse homologue of the human MYOC (GLC1A) gene in adult brain. Brain Res. Mol. Brain. Res. 68, 64–72 ( 1999).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank D. Nishimura for critical suggestions; G. Hageman and the Lions Eye Bank for the kind gift of the human tissue; A. Kanis and J. Fingert for ocular tissue collection and dissection, J.J.-C. Lin and R. Reiter for use of the in situ hybridization facility; the Blodi Ocular Pathology Laboratory for tissue processing and embedding; J. Ross for technical assistance with tissue sectioning, photography and computer imaging; and E. De Castro, J. Huang, D. Marks and T. Aleman for help with all the patient-related aspects of the study. V.C.S. is an associate investigator of the Howard Hughes Medical Institute. This work was supported in part by Public Health Service research grants (EY11298, EY05627, EY10539, EY10564 and EY10900), the Foundation Fighting Blindness, the Grousbeck Family Foundation, the Carver Charitable Trusts and the Horvitz Family Foundation.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Val C. Sheffield.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Haider, N., Jacobson, S., Cideciyan, A. et al. Mutation of a nuclear receptor gene, NR2E3, causes enhanced S cone syndrome, a disorder of retinal cell fate. Nat Genet 24, 127–131 (2000). https://doi.org/10.1038/72777

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/72777

This article is cited by

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