Document Detail

RNA splicing is responsive to MBNL1 dose.
MedLine Citation:
PMID:  23166594     Owner:  NLM     Status:  MEDLINE    
Myotonic dystrophy (DM1) is a highly variable, multi-system disorder resulting from the expansion of an untranslated CTG tract in DMPK. In DM1 expanded CUG repeat RNAs form hairpin secondary structures that bind and aberrantly sequester the RNA splice regulator, MBNL1. RNA splice defects resulting as a consequence of MBNL1 depletion have been shown to play a key role in the development of DM1 pathology. In patient populations, both the number and severity of DM1 symptoms increase broadly as a function of CTG tract length. However significant variability in the DM1 phenotype is observed in patients encoding similar CTG repeat numbers. Here we demonstrate that a gradual decrease in MBNL1 levels results both in the expansion of the repertoire of splice defects and an increase in the severity of the splice alterations. Thus, MBNL1 loss does not have an all or none outcome but rather shows a graded effect on the number and severity of the ensuing splice defects. Our results suggest that once a critical threshold is reached, relatively small dose variations of free MBNL1 levels, which may reflect modest changes in the size of the CUG tract or the extent of hairpin secondary structure formation, can significantly alter the number and severity of splice abnormalities and thus contribute to the phenotype variability observed in DM1 patients.
Sonali P Jog; Sharan Paul; Warunee Dansithong; Stephanie Tring; Lucio Comai; Sita Reddy
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-11-15
Journal Detail:
Title:  PloS one     Volume:  7     ISSN:  1932-6203     ISO Abbreviation:  PLoS ONE     Publication Date:  2012  
Date Detail:
Created Date:  2012-11-20     Completed Date:  2013-05-06     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  101285081     Medline TA:  PLoS One     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e48825     Citation Subset:  IM    
Department of Biochemistry and Molecular Biology, Institute for Genetic Medicine, University of Southern California, Los Angeles, California, USA.
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MeSH Terms
Blotting, Western
Muscle, Skeletal / metabolism
Myotonic Dystrophy / genetics*,  pathology
RNA Splicing / genetics*
RNA, Small Interfering / genetics
RNA-Binding Proteins / genetics,  metabolism*
Trinucleotide Repeat Expansion / genetics
Grant Support
R01 NS060839-03/NS/NINDS NIH HHS; R01 NS50861-04/NS/NINDS NIH HHS
Reg. No./Substance:
0/MBNL1 protein, human; 0/RNA, Small Interfering; 0/RNA-Binding Proteins

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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