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 RNA splicing abnormalities that are characteristic of DM disease. Our results support the hypothesis that manifestations of DM can result from sequestration of specific RNA binding proteins by a repetitive element expansion in a mutant RNA.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Alternative Splicing
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Animals
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CELF1 Protein
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Cataract / etiology
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Cataract / pathology
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Cell Nucleus / metabolism
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Chloride Channels / genetics
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Chloride Channels / metabolism
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DNA-Binding Proteins
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Disease Models, Animal
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Electromyography
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Exons
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Gene Targeting
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Introns
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Muscle Fibers, Skeletal / pathology
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Muscle Relaxation
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Muscle, Skeletal / pathology
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Muscle, Skeletal / physiopathology
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Myocardium / metabolism
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Myotonic Dystrophy / genetics*
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Myotonic Dystrophy / pathology
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Myotonic Dystrophy / physiopathology*
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Protein Isoforms
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RNA Splicing
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RNA-Binding Proteins / genetics*
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RNA-Binding Proteins / metabolism
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RNA-Binding Proteins / physiology*
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Reverse Transcriptase Polymerase Chain Reaction
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Trinucleotide Repeat Expansion
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Troponin T / genetics
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Troponin T / metabolism
Substances
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CELF1 Protein
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CELF1 protein, human
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CLC-1 channel
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Chloride Channels
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DNA-Binding Proteins
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Mbnl1 protein, mouse
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Protein Isoforms
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RNA-Binding Proteins
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Troponin T