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:

Total colourblindness is caused by mutations in the gene encoding the α-subunit of the cone photoreceptor cGMP-gated cation channel

Nature Genetics volume 19, pages 257–259 (1998)Cite this article

Abstract

Total colourblindness (OMIM 216900), also referred to as rod monochromacy (RM) or complete achromatopsia, is a rare, autosomal recessive inherited and congenital disorder characterized by photophobia, reduced visual acuity, nystagmus and the complete inability to discriminate between colours1. Electroretinographic recordings show that in RM, rod photoreceptor function is normal, whereas cone photoreceptor responses are absent. The locus for RM has been mapped to chromosome 2q11 (ref. 2), however the gene underlying RM has not yet been identified. Recently, a suitable candidate gene, CNGA3, encoding the α-subunit of the cone photoreceptor cGMP-gated cation channel, a key component of the phototransduction pathway, has been cloned and assigned to human chromosome 2q11 (Refs 3,4). We report the identification of missense mutations in CNGA3 in five families with RM. Homozygous mutations are present in two families, whereas the remaining families show compound heterozygous mutations. In all cases, the segregation pattern of the mutations is consistent with the autosomal recessive inheritance of the disease and all mutations affect amino acids that are highly conserved among cyclic nucleotide gated channels (CNG) in various species. This is the first report of a colour vision disorder caused by defects other than mutations in the cone pigment genes, and implies at least in this instance a common genetic basis for phototransduction in the three different cone photoreceptors of the human retina.

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: Sequences of mutations found in selected RM patients.
Figure 2: RFLP-based co-segregation analysis of CNGA3 mutations within three selected pedigrees.
Figure 3: Putative topology of the human cone cGMP-gated cation channel α-subunit.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Sharpe, L.T. & Nordby, K. Total colour blindness: An introduction . in Night vision: basic, clinical and applied aspects (eds Hess, R.F., Sharpe, L.T. & Nordby, K., Cambridge University Press, Cambridge, 1990).

    Google Scholar 

  2. Arbour, N. et al. Homozygosity mapping of achromatopsia to chromosome 2 using DNA pooling. Hum. Mol. Genet. 6, 689–694 (1997).

    Article  CAS  Google Scholar 

  3. Yu, W.-P., Grunwald, M.E. & Yau, K.-W. Molecular cloning, functional expression and chromosomal localization of a human homolog of the cyclic nucleotide-gated ion channel of retinal cone photoreceptors . FEBS Lett. 393, 211–215 (1996).

    Article  CAS  Google Scholar 

  4. Wissinger, B. et al. Cloning, chromosomal localization and functional expression of the gene encoding the α-subunit of the cGMP-gated channel in human cone photoreceptors . Eur. J. Neurosci. 9, 2512– 2521 (1997).

    Article  CAS  Google Scholar 

  5. Wissinger, B. et al. Human rod monochromacy: linkage analysis and mapping of a cone photoreceptor expressed candidate gene on chromosome 2q11. Genomics (in press).

  6. Baumann, A., Frings, S., Godde, M., Seifert, R. & Kaupp, U.B. Primary structure and functional expression of a drosophila cyclic nucleotide-gated channel present in eyes and antennae. EMBO J. 13, 5040–5050 ( 1994).

    Article  CAS  Google Scholar 

  7. Coburn, C.M. & Bargmann, C.I. A putative cyclic nucleotide-gated channel is required for sensory development and function in C. elegans . Neuron 17, 695–706 (1996).

    Article  CAS  Google Scholar 

  8. Weyand, I. et al. Cloning and functional expression of a cyclic-nucleotide-gated channel from mammalian sperm. Nature 368, 859– 863 (1994).

    Article  CAS  Google Scholar 

  9. Bönigk, W. et al. Rod and cone photoreceptor cells express distinct genes for cGMP-gated channels . Neuron 10, 865–877 (1993).

    Article  Google Scholar 

  10. Pittler, S.J. et al. Primary structure and chromosomal localization of human and mouse rod photoreceptor cGMP-gated cation channel. J. Biol. Chem. 267, 6257–6262 (1992).

    CAS  Google Scholar 

  11. Zagotta, W.N. & Siegelbaum, S.A. Structure and function of the cyclic nucleotide-gated channels. Annu. Rev. Neurosci. 19, 235–263 (1996).

    Article  CAS  Google Scholar 

  12. Brown, R.L., Gramling, R., Bert, R.J. & Karpen, J.W. Cyclic GMP contact points within the 63kDa subunit and a 240kDa associated protein of retinal rod cGMP-activated channels. Biochemistry 34, 8365–8370 (1995).

    Article  CAS  Google Scholar 

  13. Dryja, T.P. et al. Mutations in the gene encoding the α-subunit of the rod cGMP-gated channel in autosomal recessive retinitis pigmentosa. Proc. Natl Acad. Sci. USA 92, 10177–10181 ( 1995).

    Article  CAS  Google Scholar 

  14. Dryja, T.P., Berson, E.L., Rao, V.R. & Oprian, D.D. Heterozygous missense mutation in the rhodopsin gene as a cause of congenital stationary night blindness. Nature Genet. 4, 280– 283 (1993).

    Article  CAS  Google Scholar 

  15. Fain, G.L. & Lisman, J.E. Photoreceptor degeneration in vitamin A deprivation and retinitis pigmentosa: the equivalent light hypothesis. Exp. Eye Res. 57, 335–340 (1993).

    Article  CAS  Google Scholar 

  16. Payne, A.M. et al. A mutation in guanylate cyclase activator 1A (GUCA1A) in an autosomal dominant cone dystrophy pedigree mapping to a new locus on chromosome 6p21.1. Hum. Mol. Genet. 7, 273–277 (1998).

    Article  CAS  Google Scholar 

  17. Semple-Dowland, S.L., Lee, N.R., Van Hooser, P., Palczewski, K. & Baehr, W. A null mutation in the photoreceptor guanylate cyclase gene causes the retinal degeneration chicken phenotype. Proc. Natl Acad. Sci. USA 95, 1271– 1276 (1998).

    Article  Google Scholar 

  18. Sharpe, L.T. & Nordby, K. The photoreceptors in the achromat . in Night vision: basic, clinical and applied aspects (eds Hess, R.F., Sharpe, L.T. & Nordby, K., Cambridge University Press, Cambridge, 1990).

    Google Scholar 

Download references

Acknowledgements

This work has been supported by grants of the Deutsche Forschungsgemeinschaft and the Bundesministerium für Bildung, Wissenschaft, Forschung und Technologie to B.W. (SFB430 A5) and to L.T.S. (IKFZ IB3), respectively, and in part from grants of the NIH (EY-05627) and the Foundation Fighting Blindness to S.G.J. We would like to thank D. Hanna and M. Anastasi for providing RM families for investigation.

Author information

Authors and Affiliations

  1. Molekulargenetisches Labor, Universitäts-Augenklinik Tübingen, Schleichstr. 12-16, Tübingen, 72076, Germany

    Susanne Kohl, Ian Giddings & Bernd Wissinger

  2. Psychophysisches Labor, Forschungsstelle für Experimentelle Ophthalmologie, Universitäts-Augenklinik Tübingen, Schleichstr. 12-16, Tübingen, 72076, Germany

    Herbert Jägle & Lindsay T. Sharpe

  3. Abteilung für Pathophysiologie des Sehens und Neuroophthalmologie, Universitäts-Augenklinik Tübingen, Schleichstr. 12-16, Tübingen, 72076, Germany

    Susanne Kohl, Ian Giddings, Herbert Jägle, Eckhart Apfelstedt-Sylla, Eberhart Zrenner & Lindsay T. Sharpe

  4. Institut für Pathologie, Universität Tübingen, Liebermeisterstr. 8, Tübingen, 72076, Germany

    Tim Marx

  5. Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, 19104-2689, Pennsylvania, USA

    Samuel G. Jacobson

Authors
  1. Susanne Kohl
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tim Marx
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ian Giddings
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Herbert Jägle
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Samuel G. Jacobson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Eckhart Apfelstedt-Sylla
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Eberhart Zrenner
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Lindsay T. Sharpe
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Bernd Wissinger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bernd Wissinger.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kohl, S., Marx, T., Giddings, I. et al. Total colourblindness is caused by mutations in the gene encoding the α-subunit of the cone photoreceptor cGMP-gated cation channel. Nat Genet 19, 257–259 (1998). https://doi.org/10.1038/935

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/935

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