Molecular pathogenesis of achromatopsia associated with mutations in the cone cyclic nucleotide-gated channel CNGA3 subunit.

Cone photoreceptor cyclic nucleotide-gated (CNG) channel is essential for central and color vision and visual acuity. Mutations in the cone channel subunits CNGA3 and CNGB3 are linked to achromatopsia and progressive cone dystrophy in humans. Over 50 mutations have been identified in the CNGA3 subunit. The R277C and R283W substitutions are among the most frequently occurring mutations. This study investigated the defects of these two mutations using a heterologous expression system. The wild type and mutant CNGA3 were expressed in HEK293 cells, the channel's expression and cellular localization were examined by immunoblotting and immunofluorecences labeling, and activity of the channel was evaluated by ratiometric [Ca(2+)](i) measurements and by electrophysiological recordings. By using this model system we observed dysfunction of the mutant channels. Co-expression of the mutant channel with the wild type subunit did not affect the wild type channel's activity. Immunoflurescence labeling showed apparent cytosol aggregation of the immunoreactivity in cells expressing the mutants. Thus these disease-causing mutations appear to induce loss of function by impairing the channel cellular trafficking and plasma membrane targeting. Therapeutic supplementation of the wild type transgene may help correct the visual disorders caused by these two mutations.