title: LDB3 splicing abnormalities are specific to skeletal muscles of patients with myotonic dystrophy type 1 and alter its PKC binding affinity.
abstract: 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.
authors.affiliation: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Yamashita
authors.affiliation: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan; Division of Neurology, Department of Medicine, Jichi Medical University, Shomotsuke, Japan. Electronic address: tohrum@jichi.ac.jp.
authors.forename: Tohru
authors.initials: T
authors.lastname: Matsuura
authors.affiliation: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Tatsuaki
authors.initials: T
authors.lastname: Kurosaki
authors.affiliation: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Amakusa
authors.affiliation: Department of Frontier Health Sciences, Graduate School of Human Health Sciences, Tokyo Metropolitan University, Tokyo, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Kinoshita
authors.affiliation: Department of Neurology, Aichi Medical University School of Medicine, Aichi, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Ibi
authors.affiliation: Department of Neurology, Aichi Medical University School of Medicine, Aichi, Japan.
authors.forename: Ko
authors.initials: K
authors.lastname: Sahashi
authors.affiliation: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Kinji
authors.initials: K
authors.lastname: Ohno
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism*; D000328:Adult; D000368:Aged; D002648:Child; D015331:Cohort Studies; D005091:Exons; D005260:Female; D006801:Humans; D007223:Infant; D007527:Isoenzymes; D060588:LIM Domain Proteins / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism*; D009135:Muscular Diseases / Q000235:genetics / Q000378:metabolism; D009223:Myotonic Dystrophy / Q000235:genetics* / Q000378:metabolism*; D020033:Protein Isoforms; D011493:Protein Kinase C / Q000378:metabolism*; D012326:RNA Splicing; D014162:Transfection; D019680:Trinucleotide Repeat Expansion; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D007527:Isoenzymes; C120696:LDB3 protein, human; D060588:LIM Domain Proteins; D020033:Protein Isoforms; D011493:Protein Kinase C
keywords: CUG triplet repeat RNA-binding protein; LIM domain binding 3; Muscleblind-like 1; Myotonic dystrophy type 1; Protein kinase C