1. Facioscapulohumeral muscular dystrophy in mice overexpressing FRG1
- Author
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Michael R. Green, Chiara Zecca, Rossella Tupler, Alessandro Prelle, Maurizio Moggio, Roberto Bottinelli, Davide Gabellini, Giuseppe D'Antona, Raffaella Adami, Maria Antonietta Pellegrino, Patrizia Ciscato, and Barbara Angeletti
- Subjects
musculoskeletal diseases ,FSHD ,FRG1 ,mouse model ,Physical Exertion ,Mice, Transgenic ,Biology ,medicine.disease_cause ,Cell Line ,Mice ,Atrophy ,DUX4 ,Weight Loss ,medicine ,Facioscapulohumeral muscular dystrophy ,Animals ,Humans ,Kyphosis ,Transgenes ,Muscular dystrophy ,Muscle, Skeletal ,Genetics ,Mutation ,Multidisciplinary ,Alternative splicing ,Microfilament Proteins ,Skeletal muscle ,Proteins ,RNA-Binding Proteins ,Organ Size ,medicine.disease ,Muscular Dystrophy, Facioscapulohumeral ,Mice, Inbred C57BL ,Alternative Splicing ,medicine.anatomical_structure ,RNA splicing ,Cancer research ,Female - Abstract
Facioscapulohumeral muscular dystrophy is a human muscle disorder linked to deletions of a repeat unit on chromosome 4. An experiment in which transgenic mice were engineered to overexpress three skeletal muscle genes linked to this deletion shows that overexpression of one of them, FRG1, causes the signs of muscular dystrophy. Too much FRG1 leads to abnormal splicing of pre-mRNAs in skeletal muscle. Future studies will explore how this leads to abnormal spine curvature and other symptoms. And the availability of a mouse model for this type of muscular dystrophy will be of value in evaluating therapeutic strategies. Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant neuromuscular disorder that is not due to a classical mutation within a protein-coding gene1,2. Instead, almost all FSHD patients carry deletions of an integral number of tandem 3.3-kilobase repeat units, termed D4Z4, located on chromosome 4q35 (ref. 3). D4Z4 contains a transcriptional silencer whose deletion leads to inappropriate overexpression in FSHD skeletal muscle of 4q35 genes located upstream of D4Z4 (ref. 4). To identify the gene responsible for FSHD pathogenesis, we generated transgenic mice selectively overexpressing in skeletal muscle the 4q35 genes FRG1, FRG2 or ANT1. We find that FRG1 transgenic mice develop a muscular dystrophy with features characteristic of the human disease; by contrast, FRG2 and ANT1 transgenic mice seem normal. FRG1 is a nuclear protein and several lines of evidence suggest it is involved in pre-messenger RNA splicing5,6,7. We find that in muscle of FRG1 transgenic mice and FSHD patients, specific pre-mRNAs undergo aberrant alternative splicing. Collectively, our results suggest that FSHD results from inappropriate overexpression of FRG1 in skeletal muscle, which leads to abnormal alternative splicing of specific pre-mRNAs.
- Published
- 2005