Corcos Laurent, Solier Stéphanie
Inserm U.613, Faculté de Médecine, 22, avenue Camille Desmoulins, 29238 Brest Cedex 3, France.
Med Sci (Paris). 2005 Mar;21(3):253-60. doi: 10.1051/medsci/2005213253.
Pre-mRNA splicing operates towards at least 95 % of the transcript pool. It is subjected to a large number of variations, collectively regrouped under the term of alternative mRNA splicing, which occurs, on average, 6 to 8 times per pre-mRNA molecule. Consequently, many more proteins may be encoded from a single gene, which may satisfy a physiological need, or mark a pathological adaptation. The identification of mutations in sequences required for splicing, both constitutive and alternative, or for their control, has permitted to determine the causes of qualitative or quantitative variations in transcript levels associated with inherited diseases or cancer development. A number of molecular approaches have been undertaken to try to compensate for the effect of deleterious splicing mutations and to restore, at least in part, sufficient amounts of either the normal or a surrogate transcript. These include overexpression of splicing proteins, improvement of their activity by post-translational modification, splice-site increased or decreased usage, and RNA-mediated trans-splicing. Using such approaches, phenotypic improvements have been obtained in animal models, carrying new hopes for the development of therapeutic strategies aimed at correcting both inherited and acquired diseases that involve pre-mRNA splicing defects.
前体mRNA剪接作用于至少95%的转录本库。它会经历大量的变异，这些变异统称为可变mRNA剪接，平均每个前体mRNA分子会发生6到8次。因此，一个基因可能编码更多的蛋白质，这可能满足生理需求，也可能标志着病理适应。对组成型和可变剪接及其调控所需序列中的突变进行鉴定，有助于确定与遗传疾病或癌症发展相关的转录水平定性或定量变化的原因。人们已经采取了多种分子方法来试图补偿有害剪接突变的影响，并至少部分恢复正常转录本或替代转录本的足够数量。这些方法包括剪接蛋白的过表达、通过翻译后修饰提高其活性、增加或减少剪接位点的使用以及RNA介导的反式剪接。利用这些方法，在动物模型中已经获得了表型改善，这为开发旨在纠正涉及前体mRNA剪接缺陷的遗传和后天疾病的治疗策略带来了新的希望。
