Genetic basis of total colourblindness among the Pingelapese islanders

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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.