Abstract
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 splicing5-7. 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.
| Original language | English |
|---|---|
| Pages (from-to) | 973-977 |
| Number of pages | 5 |
| Journal | Nature |
| Volume | 439 |
| Issue number | 7079 |
| DOIs | |
| Publication status | Published - Feb 23 2006 |
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Facioscapulohumeral muscular dystrophy in mice overexpressing FRG1. / Gabellini, Davide; D'Antona, Giuseppe; Moggio, Maurizio; Prelle, Alessandro; Zecca, Chiara; Adami, Raffaella; Angeletti, Barbara; Ciscato, Patrizia; Pellegrino, Maria Antonietta; Bottinelli, Roberto; Green, Michael R.; Tupler, Rossella.
In: Nature, Vol. 439, No. 7079, 23.02.2006, p. 973-977.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Facioscapulohumeral muscular dystrophy in mice overexpressing FRG1
AU - Gabellini, Davide
AU - D'Antona, Giuseppe
AU - Moggio, Maurizio
AU - Prelle, Alessandro
AU - Zecca, Chiara
AU - Adami, Raffaella
AU - Angeletti, Barbara
AU - Ciscato, Patrizia
AU - Pellegrino, Maria Antonietta
AU - Bottinelli, Roberto
AU - Green, Michael R.
AU - Tupler, Rossella
PY - 2006/2/23
Y1 - 2006/2/23
N2 - 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 splicing5-7. 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.
AB - 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 splicing5-7. 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.
UR - http://www.scopus.com/inward/record.url?scp=33644522383&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33644522383&partnerID=8YFLogxK
U2 - 10.1038/nature04422
DO - 10.1038/nature04422
M3 - Article
C2 - 16341202
AN - SCOPUS:33644522383
VL - 439
SP - 973
EP - 977
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7079
ER -