Title

Facioscapulohumeral muscular dystrophy in mice overexpressing FRG1

UMMS Affiliation

Program in Gene Function and Expression; Program in Molecular Medicine

Date

2-13-2006

Document Type

Article

Medical Subject Headings

Alternative Splicing; Animals; Cell Line; Female; Humans; Kyphosis; Mice; Mice, Inbred C57BL; Mice, Transgenic; Muscle, Skeletal; Muscular Dystrophy,; Facioscapulohumeral; Organ Size; Physical Exertion; Proteins; Transgenes; Weight Loss

Disciplines

Genetics and Genomics

Abstract

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

Rights and Permissions

Citation: Nature. 2006 Feb 23;439(7079):973-7. Epub 2005 Dec 11. Link to article on publisher's site

Related Resources

Link to Article in PubMed

PubMed ID

16341202