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.

Genetic basis of total colourblindness among the Pingelapese islanders

Nature Genetics volume 25, pages 289–293 (2000)Cite this article

Abstract

Complete achromatopsia is a rare, autosomal recessive disorder characterized by photophobia, low visual acuity, nystagmus and a total inability to distinguish colours. In this disease, cone photoreceptors, the retinal sensory neurons mediating colour vision, seem viable but fail to generate an electrical response to light1,2. Achromatopsia, or rod monochromatism, was first mapped to 2p11–2q12 (MIM 216900; ref. 3), where it is associated with missense mutations in CNGA3 (ref. 4). CNGA3 encodes the α-subunit of the cone cyclic nucleotide-gated cation channel, which generates the light-evoked electrical responses of cone photoreceptors5,6,7. A second locus at 8q21–q22 has been identified among the Pingelapese islanders of Micronesia8,9, who have a high incidence of recessive achromatopsia10,11 (MIM 262300). Here we narrow the achromatopsia locus to 1.4 cM and show that Pingelapese achromatopsia segregates with a missense mutation at a highly conserved site in CNGB3, a new gene that encodes the β-subunit of the cone cyclic nucleotide-gated cation channel. Two independent frameshift deletions establish that achromatopsia is the null phenotype of CNGB3. Combined with earlier findings, our results demonstrate that both α- and β-subunits of the cGMP-gated channel are essential for phototransduction in all three classes of cones.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

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

Figure 1: Physical map of the achromatopsia disease interval at 8q21–q22.
Figure 2: Protein sequence and structure of CNGB3.
Figure 3: CNGB3 mutations.
Figure 4: Inheritance of deletion mutations.

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Krill, A.E. Clinical characteristics. in Hereditary Retinal and Choroidal Diseases (eds Krill, A.E. & Archer D.B.) (Harper & Row, Hagerstown, 1977).

    Google Scholar 

  2. 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 

  3. Arbour, N.C. et al. Homozygosity mapping of achromatopsia to chromosome 2 using DNA pooling. Hum. Mol. Genet. 6, 689– 684 (1997).

    Article  CAS  Google Scholar 

  4. Kohl, S. et al. Total colourblindness is caused by mutations in the gene encoding the α-subunit of the cone photoreceptor cGMP-gated cation channel. Nature Genet. 19, 257–259 (1998).

    Article  CAS  Google Scholar 

  5. 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 

  6. Yau, K.-W. et al. Cyclic nucleotide-gated channels: an expanding new family of ion channels. Proc. Natl Acad. Sci. USA 91, 3481–3483 (1994).

    Article  CAS  Google Scholar 

  7. 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 

  8. Winick, J.D. et al. Homozygosity mapping of the achromatopsia locus in the Pingelapese . Am. J. Hum. Genet. 64, 1679– 1685 (1999).

    Article  CAS  Google Scholar 

  9. Milunsky, A., Huang, X.L., Milunsky, J., DeStefano, A. & Baldwin, C.T. A locus for autosomal recessive achromatopsia on human chromosome 8q. Clin. Genet. 56, 82–85 (1999).

    Article  CAS  Google Scholar 

  10. Brody, J.A., Hussels, I.E., Brink, E. & Torres, J. Hereditary blindness among Pingelapese people of Eastern Caroline islands. Lancet 1, 1253–1257 (1970).

    Article  CAS  Google Scholar 

  11. Hussels, I.E. & Morton, N.E. Pingelap and Mokil atolls: achromatopsia . Am. J. Hum. Genet. 24, 304– 309 (1972).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Morton, N.E., Lew, R., Hussels, I.E. & Little, G.F. Pingelap and Mokil atolls: historical genetics. Am. J. Hum. Genet. 24, 277–289 (1972).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Hurd, J.N. A History and Some Traditions of Pingelap, an Atoll in the Eastern Caroline Islands Thesis, Univ. Hawaii (1977).

    Google Scholar 

  14. Sheffield, V. et al. A collection of tri- and tetranucleotide repeat markers used to generate high quality, high resolution human genome-wide linkage maps. Hum. Mol. Genet. 4, 1837–1844 (1995).

    Article  CAS  Google Scholar 

  15. Ott, J. in Analysis of Human Genetic Linkage (Johns Hopkins University Press, Baltimore, 1999).

    Google Scholar 

  16. Chen, T.-Y et al. A new subunit of cyclic nucleotide-gated channel in retinal rods. Nature 362, 764–767 (1993).

    Article  CAS  Google Scholar 

  17. Ardell, M.D. et al. The β subunit of human rod photoreceptor cGMP-gated cation channel is generated from a complex transcription unit. FEBS Lett. 389, 213–218 ( 1996).

    Article  CAS  Google Scholar 

  18. Grunwald, M.E., Yu, W.P., Yu, H.H. & Yau, K.-W. Identification of a domain on the β-subunit of the rod cGMP-gated cation channel that mediates inhibition by calcium-calmodulin. J. Biol. Chem. 273, 9148–9157 (1998).

    Article  CAS  Google Scholar 

  19. Korschen, H.G. et al. Interaction of glutamic-acid-rich proteins with the cGMP signalling pathway in rod photoreceptors. Nature 400, 761–766 (1999).

    Article  CAS  Google Scholar 

  20. 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 

  21. Nathans, J., Thomas, D. & Hogness, D.S. Molecular genetics of human color vision: the genes encoding blue, green and red pigments. Science 232, 193–202 (1986).

    Article  CAS  Google Scholar 

  22. Altschul, S.F. et al. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 25, 3389–3402 (1997).

    Article  CAS  Google Scholar 

  23. Boguski, M.S., Lowe, T.M. & Tolstoshev, C.M. dbEST-database for expressed sequence tags. Nature Genet. 4, 332–333 (1993).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the Micronesian families; patients visiting the clinic; the Old Dominion Eye Bank; N.R. Miller, J.S. Sunness and C.A. Applegate for electroretinographic results; and S. Dharmaraj, M.F. Goldberg, V.A. McKusick, J. Nathans, E.M. Sundin and R.S. Weinberg for advice and assistance. This work was funded by the Edel and Krieble Funds of the Johns Hopkins Center for Hereditary Eye Diseases (I.H.M.), The Foundation For Retinal Research (I.H.M.), The Grousbeck Family Foundation (I.H.M.), The Louise Sloan Trust (I.H.M.), a Wilmer Intramural Grant (O.H.S., I.H.M.), an Unrestricted Grant from Research to Prevent Blindness (M.F. Goldberg), NIH R01-EY10813 (O.H.S.) and a Research To Prevent Blindness Lew Wasserman Award (O.H.S.). E.D.S. is supported by a fellowship from Praxis XXI, Sub-Programa Ciencia e Tecnologia do 2 Quadro Comunitario de Apoio, Portuguese Ministry for Science and Technology.

Author information

Authors and Affiliations

  1. Laboratory of Developmental Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Olof H. Sundin, Jun-Ming Yang & Eduardo D. Silva

  2. Department of Ophthalmology, Johns Hopkins Center for Hereditary Eye Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Yingying Li, Danping Zhu, Thomas N. Mitchell, Eduardo D. Silva & Irene Hussels Maumenee

  3. Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland , USA

    Olof H. Sundin

  4. 1120 C Street SE, Washington DC, USA

    Jane N. Hurd

Authors
  1. Olof H. Sundin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jun-Ming Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yingying Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Danping Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jane N. Hurd
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Thomas N. Mitchell
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Eduardo D. Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Irene Hussels Maumenee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Olof H. Sundin.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Sundin, O., Yang, JM., Li, Y. et al. Genetic basis of total colourblindness among the Pingelapese islanders . Nat Genet 25, 289–293 (2000). https://doi.org/10.1038/77162

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/77162

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