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Alternative splicing in disease genes

疾病基因中的选择性剪接

基本信息

批准号：
18590318
负责人：
YAMADA Masao
金额：
$ 2.57万
依托单位：
National Research Institute for Child Health and Development
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590318/
关键词：
gene genome regulation of expression biotechnology proreome

项目摘要

Alternative splicing (AltSp) of pre-mRNA is an important regulatory mechanism for quantitative control of gene expression and also for generating diverse protein species. The latter is now highlighted as the human genome sequencing project has revealed a limited number of genes (20,000-25,000) in the genome, which is far less than those expected for functional complexity. Studies on AltSp have focused on cassette-type (skipping) exons, however, we and others recently revealed widespread occurrence of another type of alternative splicing where the splice acceptor or donor site is selected between adjacent two. This type of AltSp makes a subtler difference, like 3 nucleotides in mRNA and a single amino acid residue in the protein product, thus we call it as "subtle alternative splicing". We have experimentally measured the ratio of the mRNA isoforms in more than 500 cases of Subtle AltSp. Our efforts have contributed to the connection between the bioinformatics and experimental fields. N … More ow, databases on the subject appear on internet, and several reports on respective genes suggest a functional significance of the isoforms.It has been well known a considerable fraction of point mutations occurred in patients causes aberrant splicing. In some cases, a mutation near the canonical splice site abolishes the splice event using the site, and generates an aberrant splice product using a nearby cryptic site. With experiences with subtle AltSp, we assume that such aberrant splicing may be a consequence of competition between the nearby two sites, the canonical site modulated with the mutation and the cryptic site. Although many sites modulated with the mutation may loose competence as the site, other sites may retain some potential despite the mutation. We experimentally generated such sequences based on our previous results and tested the availability as the splice site. Several site sequences that were not used in the patient were indeed used when the cryptic site was further modified. This result suggests that the aberrant splicing in patients may be corrected once the cryptic splice site is modified. We have demonstrated that this indeed works by the use of RNA technology in experimental systems. Less

前体mRNA的选择性剪接（AltSp）是定量控制基因表达和产生不同蛋白质种类的重要调控机制。后者现在受到重视，因为人类基因组测序计划揭示了基因组中有限数量的基因（20 000 - 25 000），这远远低于功能复杂性的预期。AltSp的研究主要集中在盒式（跳跃）外显子，然而，我们和其他人最近发现广泛发生的另一种类型的选择性剪接，剪接受体或供体位点之间的选择相邻的两个。这种类型的AltSp使一个微妙的差异，如3个核苷酸的mRNA和一个单一的氨基酸残基的蛋白质产物，因此我们称之为“微妙的选择性剪接”。我们已经实验性地测量了500多例微妙AltSp中mRNA亚型的比例。我们的努力为生物信息学和实验领域之间的联系做出了贡献。N ...更多信息目前，有关这一课题的数据库已在互联网上出现，一些关于相应基因的报道表明了这些异构体的功能意义，众所周知，相当一部分患者发生的点突变导致了异常剪接。在一些情况下，典型剪接位点附近的突变消除使用该位点的剪接事件，并使用附近的隐蔽位点产生异常剪接产物。与微妙的AltSp的经验，我们假设，这种异常剪接可能是附近的两个站点之间的竞争的结果，典型的网站调制的突变和神秘的网站。虽然许多位点与突变的调制可能会失去作为网站的能力，其他网站可能会保留一些潜力，尽管突变。我们根据我们以前的结果实验性地产生这样的序列，并测试作为剪接位点的可用性。当隐蔽位点被进一步修饰时，确实使用了在患者中未使用的几个位点序列。这一结果表明，一旦隐蔽剪接位点被修饰，患者的异常剪接就可以得到纠正。我们已经证明，这确实是通过在实验系统中使用RNA技术。少