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


ABSTRACT: 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 Dmpk CTG expansion (CTGexp) knockin models of myotonic dystrophy type 1 (DM1). We demonstrate that skeletal muscle myoblasts and brain choroid plexus epithelial cells are particularly susceptible to Dmpk CTGexp mutations and RNA missplicing. Our results implicate dysregulation of muscle regeneration and cerebrospinal fluid homeostasis as early pathogenic events in DM1.

SUBMITTER: Nutter CA 

PROVIDER: S-EPMC6942047 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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

Nutter Curtis A CA   Bubenik Jodi L JL   Oliveira Ruan R   Ivankovic Franjo F   Sznajder Łukasz J ŁJ   Kidd Benjamin M BM   Pinto Belinda S BS   Otero Brittney A BA   Carter Helmut A HA   Vitriol Eric A EA   Wang Eric T ET   Swanson Maurice S MS  

Genes & development 20191017 23-24


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 <i>Dmpk</i> CTG expansion (CTG<sup>exp</sup>) knockin models of myotonic dystrophy type 1 (DM1). We demonstrate that skeletal muscle myoblasts  ...[more]

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