Issue |
Med Sci (Paris)
Volume 32, Number 12, Décembre 2016
|
|
---|---|---|
Page(s) | 1111 - 1119 | |
Section | M/S Revues | |
DOI | https://doi.org/10.1051/medsci/20163212015 | |
Published online | 03 January 2017 |
Altérations de l’épissage et maladies rares
Deregulation of pre-messenger RNA splicing and rare diseases
GenoSplice technology, iPEPS – ICM, Hôpital Pitié-Salpêtrière, 47-83, boulevard de l’Hôpital, 75013
Paris, France
*
pierre.delagrange@genosplice.com
La majorité des gènes codant des protéines chez l’homme sont soumis à l’épissage alternatif, le principal mécanisme permettant d’augmenter la diversité du transcriptome et du protéome. La régulation de l’épissage dépend de complexes ribonucléoprotéiques qui composent le splicéosome, ainsi que de protéines régulatrices qui reconnaissent des séquences au niveau des ARN pré-messagers. De plus en plus de mutations au niveau de ces séquences, mais également au niveau de composants du splicéosome ou de facteurs d’épissage, sont décrites pour être responsables du développement de maladies rares. Depuis ces dernières années, des approches de thérapie ciblée sont développées pour restaurer au moins partiellement des événements d’épissage altérés dans le cadre de ces maladies.
Abstract
Most of protein-coding human genes are subjected to alternative pre-mRNA splicing. This mechanism is highly regulated to precisely modulate detection of specific splice sites. This regulation is under control of the spliceosome and several splicing factors are also required to modulate the alternative usage of splice sites. Splicing factors and spliceosome components recognize splicing signals and regulatory sequences of the pre-mRNAs. These splicing sequences make splicing susceptible to polymorphisms and mutations. Examples of associations between human rare diseases and defects in pre-messenger RNA splicing are accumulating. Although many alterations are caused by mutations in splicing sequence (i.e., cis acting mutations), recent studies described the disruptive impact of mutations within spliceosome components or splicing factors (i.e., trans acting mutations). Following growing of knowledge regarding splicing regulation, several approaches have been developed to compensate for the effect of deleterious mutations and to restore sufficient amounts of functional protein.
© 2016 médecine/sciences – Inserm
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