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Probing Mechanisms of Photoreceptor Degeneration in a New Mouse Model of the Common Form of Autosomal Dominant Retinitis Pigmentosa due to P23H Opsin Mutations

机译:在P23H视蛋白突变导致的常染色体显性视网膜色素变性的常见形式的新小鼠模型中的光感受器变性的探测机制。

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摘要

Rhodopsin, the visual pigment mediating vision under dim light, is composed of the apoprotein opsin and the chromophore ligand 11-cis-retinal. A P23H mutation in the opsin gene is one of the most prevalent causes of the human blinding disease, autosomal dominant retinitis pigmentosa. Although P23H cultured cell and transgenic animal models have been developed, there remains controversy over whether they fully mimic the human phenotype; and the exact mechanism by which this mutation leads to photoreceptor cell degeneration remains unknown. By generating P23H opsin knock-in mice, we found that the P23H protein was inadequately glycosylated with levels 1–10% that of wild type opsin. Moreover, the P23H protein failed to accumulate in rod photoreceptor cell endoplasmic reticulum but instead disrupted rod photoreceptor disks. Genetically engineered P23H mice lacking the chromophore showed accelerated photoreceptor cell degeneration. These results indicate that most synthesized P23H protein is degraded, and its retinal cytotoxicity is enhanced by lack of the 11-cis-retinal chromophore during rod outer segment development.
机译:视紫红质是在暗光下介导视觉的视觉色素,由载脂蛋白视蛋白和生色团配体11-顺-视网膜组成。视蛋白基因中的P23H突变是人类致盲性疾病(常染色体显性遗传性视网膜色素变性)的最普遍原因之一。尽管已经开发了P23H培养的细胞和转基因动物模型,但是它们是否完全模仿人类表型仍存在争议。而且这种突变导致感光细胞变性的确切机制仍不清楚。通过产生P23H视蛋白敲入小鼠,我们发现P23H蛋白的糖基化程度不足,为野生型视蛋白的1-10%。此外,P23H蛋白无法在杆状感光细胞内质网中积累,反而破坏了杆状感光细胞。缺少生色团的转基因P23H小鼠显示出加速的感光细胞变性。这些结果表明,大多数合成的P23H蛋白被降解,并且由于杆外段发育过程中11-顺-视网膜生色团的缺乏而增强了其视网膜细胞毒性。

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