Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant neuromuscular disorder that is not due to a classical mutation within a protein-coding gene(1,2). 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 splicing(5-7). 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.

Facioscapulohumeral muscular dystrophy in mice overexpressing FRG1 / D., Gabellini; G., D'Antona; M., Moggio; A., Prelle; C., Zecca; R., Adami; B., Angeletti; P., Ciscato; Ma, Pellegrino; R., Bottinelli; Mr, Green; Tupler, Rossella. - In: NATURE. - ISSN 0028-0836. - STAMPA. - 439:7079(2006), pp. 973-977. [10.1038/nature04422]

Facioscapulohumeral muscular dystrophy in mice overexpressing FRG1

TUPLER, Rossella
2006

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant neuromuscular disorder that is not due to a classical mutation within a protein-coding gene(1,2). 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 splicing(5-7). 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.
2006
439
7079
973
977
Facioscapulohumeral muscular dystrophy in mice overexpressing FRG1 / D., Gabellini; G., D'Antona; M., Moggio; A., Prelle; C., Zecca; R., Adami; B., Angeletti; P., Ciscato; Ma, Pellegrino; R., Bottinelli; Mr, Green; Tupler, Rossella. - In: NATURE. - ISSN 0028-0836. - STAMPA. - 439:7079(2006), pp. 973-977. [10.1038/nature04422]
D., Gabellini; G., D'Antona; M., Moggio; A., Prelle; C., Zecca; R., Adami; B., Angeletti; P., Ciscato; Ma, Pellegrino; R., Bottinelli; Mr, Green; Tupler, Rossella
File in questo prodotto:
File Dimensione Formato  
nature04422.pdf

Solo gestori archivio

Tipologia: Versione pubblicata dall'editore
Dimensione 399.56 kB
Formato Adobe PDF
399.56 kB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

Licenza Creative Commons
I metadati presenti in IRIS UNIMORE sono rilasciati con licenza Creative Commons CC0 1.0 Universal, mentre i file delle pubblicazioni sono rilasciati con licenza Attribuzione 4.0 Internazionale (CC BY 4.0), salvo diversa indicazione.
In caso di violazione di copyright, contattare Supporto Iris

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/305323
Citazioni
  • ???jsp.display-item.citation.pmc??? 98
  • Scopus 178
  • ???jsp.display-item.citation.isi??? 170
social impact