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RNA Splicing Is Responsive to MBNL1 Dose
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 a...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3499511/ https://www.ncbi.nlm.nih.gov/pubmed/23166594 http://dx.doi.org/10.1371/journal.pone.0048825 |
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author | Jog, Sonali P. Paul, Sharan Dansithong, Warunee Tring, Stephanie Comai, Lucio Reddy, Sita |
author_facet | Jog, Sonali P. Paul, Sharan Dansithong, Warunee Tring, Stephanie Comai, Lucio Reddy, Sita |
author_sort | Jog, Sonali P. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-3499511 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-34995112012-11-19 RNA Splicing Is Responsive to MBNL1 Dose Jog, Sonali P. Paul, Sharan Dansithong, Warunee Tring, Stephanie Comai, Lucio Reddy, Sita PLoS One Research Article 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. Public Library of Science 2012-11-15 /pmc/articles/PMC3499511/ /pubmed/23166594 http://dx.doi.org/10.1371/journal.pone.0048825 Text en © 2012 Jog et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Jog, Sonali P. Paul, Sharan Dansithong, Warunee Tring, Stephanie Comai, Lucio Reddy, Sita RNA Splicing Is Responsive to MBNL1 Dose |
title | RNA Splicing Is Responsive to MBNL1 Dose |
title_full | RNA Splicing Is Responsive to MBNL1 Dose |
title_fullStr | RNA Splicing Is Responsive to MBNL1 Dose |
title_full_unstemmed | RNA Splicing Is Responsive to MBNL1 Dose |
title_short | RNA Splicing Is Responsive to MBNL1 Dose |
title_sort | rna splicing is responsive to mbnl1 dose |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3499511/ https://www.ncbi.nlm.nih.gov/pubmed/23166594 http://dx.doi.org/10.1371/journal.pone.0048825 |
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