Molecular basis of an inherited form of incomplete achromatopsia.
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.
Tränkner
Dimitri
D
Institut für Biologische Informationsverarbeitung, Forschungszentrum Jülich, 52425 Jülich, Germany. d.traenkner@fz-juelich.de
Jägle
Herbert
H
Kohl
Susanne
S
Apfelstedt-Sylla
Eckart
E
Sharpe
Lindsay T
LT
Kaupp
U Benjamin
UB
Zrenner
Eberhart
E
Seifert
Reinhard
R
Wissinger
Bernd
B
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
C415904:CNGB3 protein, human; D054815:Cyclic Nucleotide-Gated Cation Channels; D007473:Ion Channels; D002118:Calcium