Tränkner Dimitri, Jägle Herbert, Kohl Susanne, Apfelstedt-Sylla Eckart, Sharpe Lindsay T, Kaupp U Benjamin, Zrenner Eberhart, Seifert Reinhard, Wissinger Bernd
Institut für Biologische Informationsverarbeitung, Forschungszentrum Jülich, 52425 Jülich, Germany.
J Neurosci. 2004 Jan 7;24(1):138-47. doi: 10.1523/JNEUROSCI.3883-03.2004.
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.
编码视锥光感受器环核苷酸门控（CNG）通道的CNGA3和CNGB3亚基的基因突变与常染色体隐性遗传性全色盲相关。在此，我们分析了两名具有残余视锥功能的同胞全色盲的分子基础。心理物理学和视网膜电图分析表明，视锥系统的光敏感度降低，且视锥细胞到二级神经元的信号传递受到干扰。两名同胞均携带两个突变的CNGA3等位基因，这些等位基因产生具有不同单氨基酸替代的通道亚基。异源表达显示，只有一种突变体形成功能性通道，尽管其特性发生了显著改变，包括Ca2+阻断和通透的变化。令人惊讶的是，该突变亚基与CNGB3的共表达挽救了通道表型，但Ca2+相互作用除外。我们认为这些改变是导致光敏感度和突触传递受到干扰的原因。
