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      Functional analysis of rod monochromacy-associated missense mutations in the CNGA3 subunit of the cone photoreceptor cGMP-gated channel.

      Biochemical and Biophysical Research Communications
      Cell Line, Cloning, Molecular, Color Vision Defects, Cyclic GMP, metabolism, Cyclic Nucleotide-Gated Cation Channels, Dimerization, Dose-Response Relationship, Drug, Humans, Ion Channels, chemistry, physiology, Kinetics, Mutation, Mutation, Missense, Patch-Clamp Techniques, Photoreceptor Cells, Retinal Cone Photoreceptor Cells, Retinal Rod Photoreceptor Cells

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          Abstract

          Thirty-nine missense mutations, which had been identified in rod monochromacy or related disorders, in the CNGA3 subunit of cone photoreceptor cGMP-gated channels were analyzed. HEK293 cells were transfected with cDNA of the human CNGA3 subunit harboring each of these mutations in an expression vector. Patch-clamp recordings demonstrated that 32 of the 39 mutants did not show cGMP-activated current, suggesting that these 32 mutations cause a loss of function of the channels. From the remaining 7 mutants that showed cGMP-activated current, two mutations in the cyclic nucleotide-binding domain, T565M or E593K, were further studied. The half-maximal activating concentration (K(1/2)) for cGMP in the homomeric CNGA3-T565M channels (160microM) was 17.8-fold higher than that of the homomeric wild-type CNGA3 channels (9.0microM). Conversely, the K(1/2) for cGMP in the homomeric CNGA3-E593K channels (3.0microM) was 3-fold lower than that of the homomeric wild-type CNGA3 channels. These results suggest that the T565M and E593K mutations alter the apparent affinity for cGMP of the channels to cause cone dysfunction, resulting in rod monochromacy.

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