Cell-type-specific dysregulation of RNA alternative splicing in short tandem repeat mouse knockin models of myotonic dystrophy

• Published in: Genes & development 2019-12, Vol.33 (23-24), p.1635-1640
• Main Authors: Nutter, Curtis A, Bubenik, Jodi L, Oliveira, Ruan, Ivankovic, Franjo, Sznajder, Łukasz J, Kidd, Benjamin M, Pinto, Belinda S, Otero, Brittney A, Carter, Helmut A, Vitriol, Eric A, Wang, Eric T, Swanson, Maurice S
• Format: Article
• Language: English
• Subjects: 3' Untranslated Regions - genetics; Alternative Splicing - genetics; Animals; Choroid Plexus - physiopathology; Disease Models, Animal; DNA-Binding Proteins - genetics; Gene Expression Regulation, Developmental; Gene Knock-In Techniques; Mice; Microsatellite Repeats - genetics; Muscle Fibers, Skeletal - cytology; Muscle Fibers, Skeletal - pathology; Muscle, Skeletal - cytology; Muscle, Skeletal - physiopathology; Mutation; Myotonic Dystrophy - genetics; Myotonic Dystrophy - physiopathology; Myotonin-Protein Kinase - genetics; Myotonin-Protein Kinase - metabolism; Research Communication; RNA Splicing - genetics; RNA-Binding Proteins - genetics
• ISSN: 0890-9369; 1549-5477
• DOI: 10.1101/gad.328963.119

Short tandem repeats (STRs) are prone to expansion mutations that cause multiple hereditary neurological and neuromuscular diseases. To study pathomechanisms using mouse models that recapitulate the tissue specificity and developmental timing of an STR expansion gene, we used rolling circle amplification and CRISPR/Cas9-mediated genome editing to generate CTG expansion (CTG ) knockin models of myotonic dystrophy type 1 (DM1). We demonstrate that skeletal muscle myoblasts and brain choroid plexus epithelial cells are particularly susceptible to CTG mutations and RNA missplicing. Our results implicate dysregulation of muscle regeneration and cerebrospinal fluid homeostasis as early pathogenic events in DM1.