title: Molecular basis of an inherited form of incomplete achromatopsia.
abstract: Mutations in the genes encoding the CNGA3 and CNGB3 subunits of the cyclic nucleotide-gated (CNG) channel of cone photoreceptors have been associated with autosomal recessive achromatopsia. Here we analyze the molecular basis of achromatopsia in two siblings with residual cone function. Psychophysical and electroretinographic analyses show that the light sensitivity of the cone system is lowered, and the signal transfer from cones to secondary neurons is perturbed. Both siblings carry two mutant CNGA3 alleles that give rise to channel subunits with different single-amino acid substitutions. Heterologous expression revealed that only one mutant forms functional channels, albeit with grossly altered properties, including changes in Ca2+ blockage and permeation. Surprisingly, coexpression of this mutant subunit with CNGB3 rescues the channel phenotype, except for the Ca2+ interaction. We argue that these alterations are responsible for the perturbations in light sensitivity and synaptic transmission.
authors.affiliation: Institut für Biologische Informationsverarbeitung, Forschungszentrum Jülich, 52425 Jülich, Germany. d.traenkner@fz-juelich.de
authors.forename: Dimitri
authors.initials: D
authors.lastname: Tränkner
authors.forename: Herbert
authors.initials: H
authors.lastname: Jägle
authors.forename: Susanne
authors.initials: S
authors.lastname: Kohl
authors.forename: Eckart
authors.initials: E
authors.lastname: Apfelstedt-Sylla
authors.forename: Lindsay T
authors.initials: LT
authors.lastname: Sharpe
authors.forename: U Benjamin
authors.initials: UB
authors.lastname: Kaupp
authors.forename: Eberhart
authors.initials: E
authors.lastname: Zrenner
authors.forename: Reinhard
authors.initials: R
authors.lastname: Seifert
authors.forename: Bernd
authors.initials: B
authors.lastname: Wissinger
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D003117:Color Vision Defects / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D054815:Cyclic Nucleotide-Gated Cation Channels; D004252:DNA Mutational Analysis; D004596:Electroretinography; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007473:Ion Channels / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D018408:Patch-Clamp Techniques; D010786:Photoreceptor Cells / Q000378:metabolism; D017949:Retinal Cone Photoreceptor Cells / Q000503:physiopathology; D016415:Sequence Alignment
chemical_list: C415904:CNGB3 protein, human; D054815:Cyclic Nucleotide-Gated Cation Channels; D007473:Ion Channels; D002118:Calcium