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Genetic basis of total colourblindness among the Pingelapese islanders

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.

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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.

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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.

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Correspondence to Olof H. Sundin.

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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

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