Journal
NEUROBIOLOGY OF DISEASE
Volume 69, Issue -, Pages 200-205Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2014.05.026
Keywords
Myotonic dystrophy type 1; Muscleblind-like 1; CUG triplet repeat RNA-binding protein; LIM domain binding 3; Protein kinase C
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Funding
- JSPS KAKENHI from the Ministry of Education, Culture, Sports, Science and Technology of Japan [20200078, 21390266, 23659455, 24390083, 24390221]
- Grants-in-Aid for Scientific Research [21390266, 24390083, 23659455, 20200078, 24390221] Funding Source: KAKEN
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Myotonic dystrophy type 1 (DM1) is caused by transcription of CUG repeat RNA, which causes sequestration of muscleblind-like 1 (MBNL1) and upregulation of CUG triplet repeat RNA-binding protein (CUG-BP1). In DM1, dysregulation of these proteins contributes to many aberrant splicing events, causing various symptoms of the disorder. Here, we demonstrate the occurrence of aberrant splicing of LIM domain binding 3 (LDB3) exon 11 in DM1 skeletal muscle. Exon array surveys, RT-PCR, and western blotting studies demonstrated that exon 11 inclusion was DM1 specific and could be reproduced by transfection of a minigene containing the CTG repeat expansion. Moreover, we found that the LDB3 exon 11-positive isoform had reduced affinity for PKC compared to the exon 11-negative isoform. Since PKC exhibits hyperactivation in DM1 and stabilizes CUG-BP1 by phosphorylation, aberrant splicing of LDB3 may contribute to CUG-BP1 upregulation through changes in its affinity for PKC. (C) 2014 Elsevier Inc All rights reserved.
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