Highlights
11/12/2005
Facialscapulohumeral Muscular Dystrophy in mice overexpressing FRG1.
D.Gabellini1, G.D’Antona2, M. Moggio3, A. Prelle3, C.Zecca3, R.Adami2, B.Angeletti4, P.Ciscato3, M.A.Pellegrino2, R.Bottinelli2, M.Green1, R.Tupler1,4
NATUREon line publication 11 dec. 2005
- Howard Hughes Medical Institute, University of Massachussets,MedicalSchool, Worcester, USA.
- Dip. Medicina Sperimentale, Sezione Fisiologia Umana, Unversità degli studi di Pavia.
- U.O.Neurologia - Fondazione Ospedale Maggiore Policlinico IRCCS, Milano.Centro Dino Ferrari – Universita’ degli Studi di Milano
- Biologia Generale e Genetica Medica, Università degli studi di Pavia.
Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant neuromuscular disorder that is not due to a classical mutation within protein-coding gene. Instead, almost all FSHD patients carry deletion of an integral number of tandem 3.3-Kilobase repeat units, termed D4Z4, located on chromosome 4q35. D4Z4 contains a transcriptional silencer whose deletion lead to inappropriate overexpression in FSHD skeletal muscle of4q35 genes located upstream of D4Z4.
To identify the gene responsible for FSHD pathogenesis, we generated transgenic mice selectively over-expressing FRG1,FRG2 or ANT1 in skeletal muscle. 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 splicing. We find that in muscle of FRG1 transgenic mice and FSHD patients, specific pre-mRNAs undergo aberrant alternative splicing.
Collectively our data suggest that FSHD results from inappropriate overexpression of FRG1 in skeletal muscle, which leads to abnormal alternative splicing of specific pre-mRNAs
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