Spinal muscular atrophy: SMN2 pre-mRNA splicing corrected by a U7 snRNA derivative carrying a splicing enhancer sequence.

Détails

ID Serval
serval:BIB_A5C5FF46672E
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Spinal muscular atrophy: SMN2 pre-mRNA splicing corrected by a U7 snRNA derivative carrying a splicing enhancer sequence.
Périodique
Molecular therapy : the journal of the American Society of Gene Therapy
Auteur(s)
Marquis Julien, Meyer Kathrin, Angehrn Larissa, Kampfer Sacha S., Rothen-Rutishauser Barbara, Schumperli Daniel
Statut éditorial
Publié
Date de publication
08/2007
Volume
15
Numéro
8
Pages
1479-1486
Langue
anglais
Résumé
Spinal muscular atrophy (SMA) is a lethal hereditary disease caused by homozygous deletion/inactivation of the survival of motoneuron 1 (SMN1) gene. The nearby SMN2 gene, despite its identical coding capacity, is only an incomplete substitute, because a single nucleotide difference impairs the inclusion of its seventh exon in the messenger RNA (mRNA). This splicing defect can be corrected (transiently) by specially designed oligonucleotides. Here we have developed a more permanent correction strategy based on bifunctional U7 small nuclear RNAs (snRNAs). These carry both an antisense sequence that allows specific binding to exon 7 and a splicing enhancer sequence that will improve the recognition of the targeted exon. When expression cassettes for these RNAs are stably introduced into cells, the U7 snRNAs become incorporated into small nuclear ribonucleoprotein (snRNP) particles that will induce a durable splicing correction. We have optimized this strategy to the point that virtually all SMN2 pre-mRNA becomes correctly spliced. In fibroblasts from an SMA patient, this approach induces a prolonged restoration of SMN protein and ensures its correct localization to discrete nuclear foci (gems).
Mots-clé
Base Sequence, Humans, Cell Line, Fibroblasts, Molecular Sequence Data, RNA, Small Nuclear/*genetics, SMN Complex Proteins, Survival of Motor Neuron 1 Protein, Survival of Motor Neuron 2 Protein, Cyclic AMP Response Element-Binding Protein/genetics/*metabolism, DNA, Antisense/genetics, Exons/genetics, Muscular Atrophy, Spinal/*genetics/*metabolism/pathology, Nerve Tissue Proteins/genetics/*metabolism, RNA Splicing/*genetics, RNA-Binding Proteins/genetics/*metabolism, RNA, Messenger/genetics, Time Factors
Pubmed
Création de la notice
19/02/2020 13:23
Dernière modification de la notice
19/06/2020 6:26
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