A Muscleblind Knockout Model for Myotonic Dystrophy

• Published in: Science (American Association for the Advancement of Science) 2003-12, Vol.302 (5652), p.1978-1980
• Main Authors: Kanadia, Rahul N., Johnstone, Karen A., Mankodi, Ami, Lungu, Codrin, Thornton, Charles A., Esson, Douglas, Timmers, Adrian M., Hauswirth, William W., Swanson, Maurice S.
• Format: Article
• Language: English
• Subjects: Alternative Splicing; Anatomy; Animals; Binding proteins; Biochemistry; Biological and medical sciences; Cataract - etiology; Cataract - pathology; Cataracts; CELF1 Protein; Cell Nucleus - metabolism; Chloride Channels - genetics; Chloride Channels - metabolism; Complementary DNA; Disease Models, Animal; DNA-Binding Proteins; Electromyography; Exons; Fundamental and applied biological sciences. Psychology; Gene Targeting; Genes; Genetic aspects; Hypoxia; Individualized Instruction; Introns; Mbnl1 gene; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle Fibers, Skeletal - pathology; Muscle Relaxation; Muscle, Skeletal - pathology; Muscle, Skeletal - physiopathology; Muscular dystrophy; Muscular system; Myocardium - metabolism; Myotonia; Myotonic dystrophy; Myotonic Dystrophy - genetics; Myotonic Dystrophy - pathology; Myotonic Dystrophy - physiopathology; neuromuscular diseases; Properties; Protein Isoforms; Proteins; Reverse Transcriptase Polymerase Chain Reaction; Ribonucleic acid; RNA; RNA Splicing; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; RNA-Binding Proteins - physiology; Sequestration (Chemistry); Site Selection; Splicing; Transcripts (Written Records); Trinucleotide Repeat Expansion; Troponin T - genetics; Troponin T - metabolism; Vertebrates: nervous system and sense organs
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1088583

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.