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Function of PAP-1,a causative gene for retinitis pigmentosa

色素性视网膜炎致病基因PAP-1的功能

基本信息

批准号：
14370551
负责人：
ARIGA Sanae
金额：
$ 8.26万
依托单位：
HOKKAIDO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370551/
关键词：
PAP-1 c-Myc RP9 retinitis pigmentosa splicing Pim-1 phosphorylation retina c-MYc

项目摘要

PAP-1, a phosphorylation target of the Pim1 oncogene, has recently been implicated as the defective gene in RP9, one type of autosomal dominant retinitis pigmentosa (adRP). However, RP9 is a rare disease and only two missense mutations have been described, so the report of a link between PAP-1 and RP9 was tentative. The precise cellular role of PAP-1 was also unknown at that time. We now report that PAP-1 localizes in nuclear speckles containing the splicing factor SC35 and interacts directly with another splicing factor, U2AF35. Furthermore we used an in vivo splicing assay to show that PAP-1 has an activity which alters the pattern of pre-mRNA splicing and that this activity is dependent on the phosphorylation state of PAP-1. We used the same splicing assay to examine the activities of two mutant forms of PAP-1 found in RP9 patients. The results showed that while one of the mutations, H137L, had no effect on splicing activity compared with that of wild-type PAP-1, the other, D170G, resulted in both a defect in splicing activity and a decreased proportion of phosphorylated PAP-1. The D17OG mutation may therefore cause RP by altering splicing of retinal genes through a decrease in PAP-1 phosphorylation These results demonstrate that PAP-1 has a role in pre-mRNA splicing and, given that three other splicing factors have been implicated in adRP, this finding provides compelling further evidence that PAP-1 is indeed the RP9 gene.

Pim1癌基因的磷酸化靶点PAP-1最近被认为是常染色体显性遗传性视网膜色素变性(Adrp)中的缺陷基因。然而，RP9是一种罕见的疾病，目前只描述了两个错义突变，因此关于PAP-1和RP9之间的联系的报告是暂定的。当时，PAP-1的确切细胞作用也是未知的。我们现在报道PAP-1定位于含有剪接因子SC35的核斑点中，并直接与另一种剪接因子U2AF35相互作用。此外，我们用体内剪接实验证明了PAP-1具有改变Pre-mRNA剪接模式的活性，并且这种活性依赖于PAP-1的磷酸化状态。我们使用相同的剪接试验来检测在RP9患者中发现的两种突变形式的PAP-1的活性。结果表明，与野生型PAP-1相比，其中一个突变H137L对剪接活性没有影响，而另一个突变D170G导致剪接活性缺陷和磷酸化PAP-1比例降低。因此，D17OG突变可能通过降低PAP-1的磷酸化改变视网膜基因的剪接而导致RP。这些结果表明PAP-1在前mRNA剪接中发挥作用，并考虑到其他三个剪接因子与adRP有关，这一发现提供了令人信服的进一步证据，证明PAP-1确实是RP9基因。