Publication Date:
2009-07-18
Description:
Genomic expansions of simple tandem repeats can give rise to toxic RNAs that contain expanded repeats. In myotonic dystrophy, the expression of expanded CUG repeats (CUGexp) causes abnormal regulation of alternative splicing and neuromuscular dysfunction. We used a transgenic mouse model to show that derangements of myotonic dystrophy are reversed by a morpholino antisense oligonucleotide, CAG25, that binds to CUGexp RNA and blocks its interaction with muscleblind-like 1 (MBNL1), a CUGexp-binding protein. CAG25 disperses nuclear foci of CUGexp RNA and reduces the overall burden of this toxic RNA. As MBNL1 is released from sequestration, the defect of alternative splicing regulation is corrected, thereby restoring ion channel function. These findings suggest an alternative use of antisense methods, to inhibit deleterious interactions of proteins with pathogenic RNAs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4109973/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4109973/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wheeler, Thurman M -- Sobczak, Krzysztof -- Lueck, John D -- Osborne, Robert J -- Lin, Xiaoyan -- Dirksen, Robert T -- Thornton, Charles A -- AR/NS48143/AR/NIAMS NIH HHS/ -- AR046806/AR/NIAMS NIH HHS/ -- K08 NS064293/NS/NINDS NIH HHS/ -- K24 AR048143/AR/NIAMS NIH HHS/ -- NIDCR-T32DE07202/DE/NIDCR NIH HHS/ -- R01 AR046806/AR/NIAMS NIH HHS/ -- R01 AR049077/AR/NIAMS NIH HHS/ -- New York, N.Y. -- Science. 2009 Jul 17;325(5938):336-9. doi: 10.1126/science.1173110.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Departments of Neurology, Pharmacology and Physiology, University of Rochester, Rochester, NY 14642, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19608921" target="_blank"〉PubMed〈/a〉
Keywords:
3' Untranslated Regions/genetics/*metabolism
;
Actins/genetics
;
Alternative Splicing
;
Animals
;
Cell Line
;
Cell Nucleus/metabolism
;
Chloride Channels/metabolism
;
DNA-Binding Proteins/*metabolism
;
Humans
;
Mice
;
Mice, Knockout
;
Mice, Transgenic
;
Myotonic Dystrophy/*drug therapy/*genetics/metabolism
;
Myotonin-Protein Kinase
;
Oligodeoxyribonucleotides, Antisense/*pharmacology/therapeutic use
;
Protein-Serine-Threonine Kinases/genetics
;
RNA, Messenger/genetics
;
RNA-Binding Proteins/*metabolism
;
Transcription, Genetic
;
*Trinucleotide Repeat Expansion
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
