Circadian clocks regulate multiple physiological processes in the eye, but their requirement for retinal health remains unclear. We previously showed that Drosophila homologs of spliceosome proteins implicated in human retinitis pigmentosa (RP), the most common genetically inherited cause of blindness, have a role in the brain circadian clock. In this study, we report circadian phenotypes in murine models of RP. We found that mice carrying a homozygous H2309P mutation in Pre-mRNA splicing factor 8 (Prpf8) display a lengthened period of the circadian wheel-running activity rhythm. We show also that the daily cycling of circadian gene expression is dampened in the retina of Prpf8-H2309P mice. Surprisingly, molecular rhythms are intact in the eye cup, which includes the retinal pigment epithelium (RPE), even though the RPE is thought to be the primary tissue affected in this form of RP. Downregulation of Prp31, another RNA splicing factor implicated in RP, leads to period lengthening in a human cell culture model. The period of circadian bioluminescence in primary fibroblasts of human RP patients is not significantly altered. Together, these studies link a prominent retinal disorder to circadian deficits, which could contribute to disease pathology.

中文翻译：

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导致色素性视网膜炎的RNA剪接因子突变导致昼夜节律失调。

昼夜节律钟调节眼睛的多个生理过程，但它们对视网膜健康的要求仍不清楚。我们以前表明，果蝇的剪接体蛋白同源物与人类视网膜色素变性（RP）有关，这是最常见的遗传性失明遗传原因，在大脑昼夜节律中起作用。在这项研究中，我们报告了RP鼠模型中的昼夜节律表型。我们发现，在Pre-mRNA剪接因子8（Prpf8）中携带纯合子H2309P突变的小鼠显示出昼夜节律性轮转活动节奏的延长。我们还显示，Prpf8-H2309P小鼠的视网膜中昼夜节律基因表达的循环受到抑制。令人惊讶的是，眼杯中的分子节律是完整的，其中包括视网膜色素上皮（RPE），即使RPE被认为是以这种形式的RP感染的主要组织。Prp31，RP牵连的另一个RNA剪接因子的下调导致人类细胞培养模型中的周期延长。人类RP患者的原代成纤维细胞中的昼夜生物发光时间没有明显改变。总之，这些研究将重要的视网膜疾病与昼夜节律缺陷联系在一起，这可能导致疾病病理。