A Muscleblind Knockout Model for Myotonic Dystrophy
Abstract
The neuromuscular disease myotonic dystrophy (DM) is caused by microsatellite repeat expansions at two different genomic loci. Mutant DM transcripts are retained in the nucleus together with the muscleblind (Mbnl) proteins, and these abnormal RNAs somehow interfere with pre-mRNA splicing regulation. Here, we show that disruption of the mouse Mbnl1 gene leads to muscle, eye, and RNAsplicing abnormalities that are characteristic of DM disease. Our results support the hypothesis that manifestations of DM can result from sequestration of specific RNAbinding proteins by a repetitive element expansion in a mutant RNA.
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In myotonic dystrophy, CTG or CCTG repeat expansions in expressed RNAs sequester MBNL proteins from their normal binding sites, altering MBNL-dependent splicing patterns.
“In myotonic dystrophy, CTG or CCTG repeat expansions in expressed RNAs sequester MBNL proteins from their normal binding sites, altering MBNL-dependent splicing patterns101–105.”
From The neurogenetics of alternative splicing (2016) · cites this paper as [101]
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- Authors
- Kanadia, R. N., Johnstone, K. A., Mankodi, A., Lungu, C., Thornton, C. A., Esson, D., Timmers, A. M., Hauswirth, W. W., & Swanson, M. S.
- Affiliations
- University of Florida Health (US)
- Corresponding author
- Swanson, Maurice S.
- ORCID
- Venue
- Science
- Published
- 2003-12-12
- Volume
- 302
- Issue
- 5652
- Pages
- 1978-1980
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2171373304
- Cited by
- 743
- References
- 22
- Citations by year
- 2026: 15 · 2025: 24 · 2024: 17 · 2023: 19 · 2022: 30 · 2021: 26 · 2020: 31 · 2019: 26 · 2018: 41 · 2017: 28 · 2016: 33 · 2015: 26 · 2014: 41 · 2013: 52 · 2012: 43
- FWCI
- 11.08
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR-48143, AR 46799, K24AR048143, R01AR046799, R01AR046806, AR46806)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- myotonic dystrophy, RNA sequestration, RNA-binding proteins, pre-mRNA splicing, mouse model, ocular abnormalities, muscle abnormalities
- MeSH terms
- CELF1 Protein, Animals, Cataract, Cell Nucleus, Disease Models, Animal, DNA-Binding Proteins, Electromyography, Exons, Introns, Mice, Inbred C57BL, Muscle Relaxation, Myocardium, Myotonic Dystrophy, RNA Splicing, RNA-Binding Proteins, Alternative Splicing, Chloride Channels, Mice, Knockout, Gene Targeting, Muscle, Skeletal, Muscle Fibers, Skeletal, Trinucleotide Repeat Expansion, Protein Isoforms, Troponin T, Reverse Transcriptase Polymerase Chain Reaction, Mice
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