Abstract
Myotonic dystrophy type 1 (DM1) is a multi-system disorder caused by CTG repeats in the myotonic dystrophy protein kinase (DMPK) gene. This leads to the sequestration of splicing factors such as muscleblind-like 1/2 (MBNL1/2) and aberrant splicing in the central nervous system. We investigated the splicing patterns of MBNL1/2 and genes controlled by MBNL2 in several regions of the brain and between the grey matter (GM) and white matter (WM) in DM1 patients using RT-PCR. Compared with amyotrophic lateral sclerosis (ALS, as disease controls), the percentage of spliced-in parameter (PSI) for most of the examined exons were significantly altered in most of the brain regions of DM1 patients, except for the cerebellum. The splicing of many genes was differently regulated between the GM and WM in both DM1 and ALS. In 7 out of the 15 examined splicing events, the level of PSI change between DM1 and ALS was significantly higher in the GM than in the WM. The differences in alternative splicing between the GM and WM may be related to the effect of DM1 on the WM of the brain.
Highlights
Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy in adults, affecting the skeletal muscle, heart, ocular lens, testis, and central nervous system (CNS)
We examined the splicing patterns of muscleblind-like 1/2 (MBNL1/2), and the other genes controlled by MBNL2, among several brain regions, and between the grey matter (GM) and white matter (WM) in DM1 patients
Compared with the ALS, percent spliced-in (PSI) for MBNL2 exon 5 were higher in all examined brain areas of DM1 and exon 8 were significantly higher in most brain areas of DM1, except for the cerebellum
Summary
Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy in adults, affecting the skeletal muscle, heart, ocular lens, testis, and central nervous system (CNS). DM1 is caused by the unstable expansion of CTG trinucleotide repeats in the 3’ untranslated region (UTR) of the myotonic dystrophy protein kinase (DMPK) gene. These CTG repeats are transcribed to CUG repeats, leading to the formation of an RNA hairpin loop. These loops form foci in the nucleus and sequester splicing factors, such as the muscleblind-like (MBNL) proteins.
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