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The Journal of Neuroscience, January 7, 2004, 24(1):138-147; doi:10.1523/JNEUROSCI.3883-03.2004

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Behavioral/Systems/Cognitive
Molecular Basis of an Inherited Form of Incomplete Achromatopsia

Dimitri Tränkner,^1 * Herbert Jägle,^2,4 * Susanne Kohl,^3,4 * Eckart Apfelstedt-Sylla,⁴ Lindsay T. Sharpe,^2,4,5 U. Benjamin Kaupp,¹ Eberhart Zrenner,⁴ Reinhard Seifert,¹ and Bernd Wissinger^3,4

¹Institut für Biologische Informationsverarbeitung, Forschungszentrum Jülich, 52425 Jülich, Germany, ²Psychophysisches Labor, ³Molekulargenetisches Labor, and ⁴Abteilung für Pathophysiologie des Sehens und Neuro-Ophthalmologie, Universitäts-Augenklinik, 72076 Tübingen, Germany, and ⁵Department of Psychology, School of Biology, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, United Kingdom

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.

Key words: CNG channel; cone photoreceptor; CNGA3 gene; CNGB3 gene; vision; Ca²⁺ permeation

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Received Aug 21, 2003; revised October 21, 2003; accepted October 21, 2003.

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