Temporal and tissue specific regulation of RP-associated splicing factor genes PRPF3, PRPF31 and PRPC8--implications in the pathogenesis of RP.
Temporal and tissue specific regulation of RP-associated splicing factor genes PRPF3, PRPF31 and PRPC8--implications in the pathogenesis of RP.
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DOI：
10.1371/journal.pone.0015860
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发表时间：
2011-01-19
期刊：
影响因子：
3.7
通讯作者：
Hu J
中科院分区：
文献类型：
--
作者：
Cao H;Wu J;Lam S;Duan R;Newnham C;Molday RS;Graziotto JJ;Pierce EA;Hu J
已发现几种普遍表达的RNA剪接基因如PRPF 3、PRP31和PRPC 8中的基因突变导致人类视网膜特异性疾病。为了理解这一有趣的现象，大多数研究都集中在测试两个主要假设上。一种假设认为，这些突变中断了视网膜特异性相互作用，这对RNA剪接很重要，这意味着视网膜中有特定的成分与这些剪接因子相互作用。第二个假设表明，这些突变对蛋白质功能只有轻微的影响，因此只影响代谢高度活跃的细胞，如视网膜光感受器。我们以PRPF3基因为例检验了第二种假设。我们分析了PRPF 3基因在小鼠中的空间和时间表达，发现它在视网膜细胞中相对于其他组织高度表达，并且其表达受到发育调节。此外，我们还发现PRP31和PRPC8以及snRNAs在视网膜细胞中高度表达。我们的数据表明，视网膜需要一个相对高水平的RNA剪接活动的最佳组织特异性的生理功能。由于RP18突变对蛋白质功能既没有削弱作用，也没有急性作用，因此我们认为视网膜变性是由于蛋白质轻度受损导致的数十年次优RNA剪接的累积效应。
Genetic mutations in several ubiquitously expressed RNA splicing genes such as PRPF3, PRP31 and PRPC8, have been found to cause retina-specific diseases in humans. To understand this intriguing phenomenon, most studies have been focused on testing two major hypotheses. One hypothesis assumes that these mutations interrupt retina-specific interactions that are important for RNA splicing, implying that there are specific components in the retina interacting with these splicing factors. The second hypothesis suggests that these mutations have only a mild effect on the protein function and thus affect only the metabolically highly active cells such as retinal photoreceptors. We examined the second hypothesis using the PRPF3 gene as an example. We analyzed the spatial and temporal expression of the PRPF3 gene in mice and found that it is highly expressed in retinal cells relative to other tissues and its expression is developmentally regulated. In addition, we also found that PRP31 and PRPC8 as well as snRNAs are highly expressed in retinal cells. Our data suggest that the retina requires a relatively high level of RNA splicing activity for optimal tissue-specific physiological function. Because the RP18 mutation has neither a debilitating nor acute effect on protein function, we suggest that retinal degeneration is the accumulative effect of decades of suboptimal RNA splicing due to the mildly impaired protein.
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