Abstract
SUMMARYMyotonic dystrophy (DM) is caused by expanded CTG/CCTG repeats, causing symptoms in skeletal muscle, heart, and central nervous system (CNS). CNS issues are debilitating and include hypersomnolence, executive dysfunction, white matter atrophy, and neurofibrillary tangles. Here, we generate RNA-seq transcriptomes from DM and unaffected frontal cortex and identify 130 high-confidence splicing changes, most occurring only in cortex, not skeletal muscle or heart. Mis-spliced exons occur in neurotransmitter receptors, ion channels, and synaptic scaffolds, and GRIP1 mis-splicing modulates kinesin association. Optical mapping of expanded CTG repeats reveals extreme mosaicism, with some alleles showing >1,000 CTGs. Mis-splicing severity correlates with CTG repeat length across individuals. Upregulated genes tend to be microglial and endothelial, suggesting neuroinflammation, and downregulated genes tend to be neuronal. Many gene expression changes strongly correlate with mis-splicing, suggesting candidate biomarkers of disease. These findings provide a framework for mechanistic and therapeutic studies of the DM CNS.
Highlights
Myotonic dystrophy (DM) is a multi-systemic, progressive disease caused by expanded CTG or CCTG repeats in the 30 UTR of the dystrophia myotonic protein kinase (DMPK) gene (DM type 1 [DM1]) (Brook et al, 1992) or the first intron of the cellular nucleic acid binding protein (CNBP) gene (DM type 2 [DM2]) (Liquori et al, 2001), respectively
Splicing dysregulation in DM1 frontal cortex (FC) exhibits a gradient of severity We performed RNA sequencing (RNA-seq) using RNA from post-mortem FC (Brodmann area 10) of 21 DM1, 4 DM2, and 8 unaffected age- and sexmatched individuals (Figure 1A; see STAR Methods)
The percentage spliced in (c) values were estimated by Mixture of Isoforms (MISO) (Katz et al, 2010), and using a threshold of at least 20% change in mean c (p < 0.01, ranksum test), 130 exons were identified to be differentially included between DM1 and unaffected individuals (Figures 1B and 1C; Table S2)
Summary
Myotonic dystrophy (DM) is a multi-systemic, progressive disease caused by expanded CTG or CCTG repeats in the 30 UTR of the dystrophia myotonic protein kinase (DMPK) gene (DM type 1 [DM1]) (Brook et al, 1992) or the first intron of the cellular nucleic acid binding protein (CNBP) gene (DM type 2 [DM2]) (Liquori et al, 2001), respectively. DM is well studied in the context of peripheral symptoms such as myotonia and muscle weakness, central nervous system (CNS) symptoms are common in DM and can contribute significantly to neurological impairment (Heatwole et al, 2012, 2015). These symptoms include hypersomnia, executive functioning deficits, memory deficits, and emotional disturbances (Modoni et al, 2008; Weber et al, 2010; Schneider-Gold et al, 2015). The molecular mechanisms driving these neurobiological changes remain largely unknown
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