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 light^1,2. 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 photoreceptors^5,6,7. A second locus at 8q21–q22 has been identified among the Pingelapese islanders of Micronesia^8,9, who have a high incidence of recessive achromatopsia^10,11 (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.