Transcriptome alterations in myotonic dystrophy frontal cortex

• Published in: Cell reports (Cambridge) Vol. 34; no. 3; p. 108634
• Main Authors: Otero, Brittney A., Poukalov, Kiril, Hildebrandt, Ryan P., Thornton, Charles A., Jinnai, Kenji, Fujimura, Harutoshi, Kimura, Takashi, Hagerman, Katharine A., Sampson, Jacinda B., Day, John W., Wang, Eric T.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19.01.2021
• Subjects: Frontal Lobe - physiopathology; Humans; Myotonic Dystrophy - genetics; Transcriptome - genetics
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.108634

Myotonic 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. [Display omitted] •DM1 RNA-seq shows mis-splicing of neurotransmitter receptors along a severity gradient•Repeats >1,000 CTGs occur in all individuals; lengths correlate with mis-splicing•GRIP1 mis-splicing perturbs kinesin association and may alter synaptic trafficking•Expression changes suggest neuroinflammation and downregulation of neuronal genes Otero et al. characterize DM1 frontal cortex transcriptomes and observe extreme CTG repeat lengths even in individuals showing modest mis-splicing. Mis-splicing is enriched in ion channels, neurotransmitter receptors, and synaptic scaffolds, in some cases potentially altering synaptic trafficking. Inferred expression signatures from microglia and endothelial cells suggest neuroinflammation.