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Mutations in CNGA3 impair trafficking or function of cone cyclic nucleotide-gated channels, resulting in achromatopsia.
CNGA3 encodes the A-subunit of the cone photoreceptor cyclic nucleotide-gated (CNG) channel, which is a crucial component of the phototransduction cascade in cone outer segments. Mutations in the CNGA3 gene have been associated with complete and incomplete forms of achromatopsia (ACHR), a congenital, autosomal recessively inherited retinal disorder characterized by lack of color discrimination, reduced visual acuity, nystagmus, and photophobia. Here we report the identification of three novel CNGA3 missense mutations in ACHR patients: c.682G>A (p.E228 K), c.1315C>T (p.R439W), and c.1405G>A (p.A469 T), and the detailed functional analyses of these new as well as five previously reported mutations (R283Q, T291R, F547L, G557R, and E590 K), in conjunction with clinical data of patients carrying these mutations, to establish genotype-phenotype correlations. The functional characterization of mutant CNGA3 channels was performed with calcium imaging and patch clamp recordings in a heterologous HEK293 cell expression system. Results were corroborated by immunostaining and colocalization experiments of the channel protein with the plasma membrane. Several mutations evoked pronounced alterations of the apparent cGMP sensitivity of mutant channels. These functional defects were fully or partially compensated by coexpressing the mutant CNGA3 subunit with the wild-type CNGB3 subunit for channels with the mutations R439W, A469 T, F547L, and E590 K. We could show that several mutant channels with agonist dose-response relationships similar to the wild-type exhibited severely impaired membrane targeting. In addition, this study presents the positive effect of reduced cell culture temperature on surface expression and functional performance of mutant CNG channels with protein folding or trafficking defects.
Authors : Reuter Peggy , Koeppen Katja , Ladewig Thomas , Kohl Susanne , Baumann Britta , Wissinger Bernd , ,
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WP1042: Nucleotide GPCRs
WP1158: Nucleotide GPCRs
WP1191: Nucleotide Metabolism
WP1364: Nucleotide GPCRs
WP146: Nucleotide Metabolism
WP1485: Interactions between CFTR and other ion channels
WP1486: Intracellular trafficking of CFTR
WP1619: Amino sugar and nucleotide sugar metabolism
WP1678: Nucleotide excision repair
WP1800: Depolarization of the Presynaptic Terminal Triggers the Opening of Calcium Channels
WP1820: Gap junction trafficking and regulation
WP1846: Membrane Trafficking
WP1980: Nucleotide Excision Repair
WP207: Nucleotide GPCRs
WP2292: Chemokine signaling pathway
WP321: Nucleotide Metabolism
WP404: Nucleotide Metabolism
WP502: Nucleotide GPCRs
WP80: Nucleotide GPCRs
WP806: Nucleotide GPCRs
WP838: Nucleotide Metabolism
WP87: Nucleotide Metabolism
WP922: Nucleotide GPCRs
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 Impaired cone function and cone degeneration resulting from CNGB3 deficiency: down-regulation of CNGA3 biosynthesis as a potential mechanism.
 Mutations in CNGA3 impair trafficking or function of cone cyclic nucleotide-gated channels, resulting in achromatopsia.
 Functional analysis of rod monochromacy-associated missense mutations in the CNGA3 subunit of the cone photoreceptor cGMP-gated channel.
 Transmembrane S1 mutations in CNGA3 from achromatopsia 2 patients cause loss of function and impaired cellular trafficking of the cone CNG channel.
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