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Myotonic dystrophy type 1 (DM1) is a multi-systemic disorder caused by a CTG trinucleotide repeat expansion (CTG exp ) in the  DMPK  gene. In skeletal muscle, nuclear sequestration of the alternative splicing factor muscleblind-like 1 (MBNL1) explains the majority of the alternative splicing defects observed in the  HSA   LR  transgenic mouse model which expresses a pathogenic range CTG exp . In the present study, we addressed the possibility that MBNL1 sequestration by CUG exp  RNA also contributes to splicing defects in the mammalian brain. We examined RNA from the brains of homozygous  Mbnl1   ΔE3/ΔE3  knockout mice using splicing-sensitive microarrays. We used RT-PCR to validate a subset of alternative cassette exons identified by microarray analysis with brain tissues from  Mbnl1   ΔE3/ΔE3  knockout mice and post-mortem DM1 patients. Surprisingly, splicing-sensitive microarray analysis of  Mbnl1   ΔE3/ΔE3  brains yielded only 14 candidates for mis-spliced exons. While we confirmed that several of these splicing events are perturbed in both  Mbnl1  knockout and DM1 brains, the extent of splicing mis-regulation in the mouse model was significantly less than observed in DM1. Additionally, several alternative exons, including  Grin1  exon 4,  App  exon 7 and  Mapt  exons 3 and 9, which have previously been reported to be aberrantly spliced in human DM1 brain, were spliced normally in the  Mbnl1  knockout brain. The sequestration of MBNL1 by CUG exp  RNA results in some of the aberrant splicing events in the DM1 brain. However, we conclude that other factors, possibly other MBNL proteins, likely contribute to splicing mis-regulation in the DM1 brain.

Muscleblind-Like 1 Knockout Mice Reveal Novel Splicing Defects in the Myotonic Dystrophy Brain