Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Facioscapulohumeral muscular dystrophy in mice overexpressing FRG1


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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Mice overexpressing FRG1 show kyphosis.
Figure 2: Skeletal muscles from FRG1 transgenic mice show dystrophic histological features.
Figure 3: Increased FRG1 transgene expression correlates with a reduction in body weight and muscle atrophy.
Figure 4: Muscles from FRG1 transgenic mice and FSHD patients show aberrant pre-mRNA splicing of selective genes.


  1. Tawil, R. Facioscapulohumeral muscular dystrophy. Curr. Neurol. Neurosci. Rep. 4, 51–54 (2004)

    Article  Google Scholar 

  2. Flanigan, K. M. in Myology (eds Engel, A. & Franzini-Armstrong, C.) 1123–1133 (McGraw Hill Professional, New York, 2004)

    Google Scholar 

  3. van Deutekom, J. C. et al. FSHD associated DNA rearrangements are due to deletions of integral copies of a 3.2 kb tandemly repeated unit. Hum. Mol. Genet. 2, 2037–2042 (1993)

    CAS  Article  Google Scholar 

  4. Gabellini, D., Green, M. R. & Tupler, R. Inappropriate gene activation in FSHD: a repressor complex binds a chromosomal repeat deleted in dystrophic muscle. Cell 110, 339–348 (2002)

    CAS  Article  Google Scholar 

  5. Kim, S. K. et al. A gene expression map for Caenorhabditis elegans. Science 293, 2087–2092 (2001)

    ADS  CAS  Article  Google Scholar 

  6. Rappsilber, J., Ryder, U., Lamond, A. I. & Mann, M. Large-scale proteomic analysis of the human spliceosome. Genome Res. 12, 1231–1245 (2002)

    CAS  Article  Google Scholar 

  7. van Koningsbruggen, S. et al. FRG1P is localised in the nucleolus, Cajal bodies, and speckles. J. Med. Genet. 41, e46 (2004)

    CAS  Article  Google Scholar 

  8. Muscat, G. E. & Kedes, L. Multiple 5′-flanking regions of the human α-skeletal actin gene synergistically modulate muscle-specific expression. Mol. Cell. Biol. 7, 4089–4099 (1987)

    CAS  Article  Google Scholar 

  9. Ricci, E. et al. Progress in the molecular diagnosis of facioscapulohumeral muscular dystrophy and correlation between the number of KpnI repeats at the 4q35 locus and clinical phenotype. Ann. Neurol. 45, 751–757 (1999)

    CAS  Article  Google Scholar 

  10. Kilmer, D. D. et al. Profiles of neuromuscular diseases. Facioscapulohumeral muscular dystrophy. Am. J. Phys. Med. Rehabil. 74, S131–S139 (1995)

    CAS  Article  Google Scholar 

  11. Deconinck, A. E. et al. Utrophin-dystrophin-deficient mice as a model for Duchenne muscular dystrophy. Cell 90, 717–727 (1997)

    CAS  Article  Google Scholar 

  12. Grady, R. M. et al. Skeletal and cardiac myopathies in mice lacking utrophin and dystrophin: a model for Duchenne muscular dystrophy. Cell 90, 729–738 (1997)

    CAS  Article  Google Scholar 

  13. Lynch, G. S., Hinkle, R. T., Chamberlain, J. S., Brooks, S. V. & Faulkner, J. A. Force and power output of fast and slow skeletal muscles from mdx mice 6–28 months old. J. Physiol. (Lond.) 535, 591–600 (2001)

    CAS  Article  Google Scholar 

  14. Durbeej, M. & Campbell, K. P. Muscular dystrophies involving the dystrophin–glycoprotein complex: an overview of current mouse models. Curr. Opin. Genet. Dev. 12, 349–361 (2002)

    CAS  Article  Google Scholar 

  15. Muntoni, F., Brockington, M. & Brown, S. C. Glycosylation eases muscular dystrophy. Nature Med. 10, 676–677 (2004)

    CAS  Article  Google Scholar 

  16. Dalkilic, I. & Kunkel, L. M. Muscular dystrophies: genes to pathogenesis. Curr. Opin. Genet. Dev. 13, 231–238 (2003)

    CAS  Article  Google Scholar 

  17. Calado, A. et al. Nuclear inclusions in oculopharyngeal muscular dystrophy consist of poly(A) binding protein 2 aggregates which sequester poly(A) RNA. Hum. Mol. Genet. 9, 2321–2328 (2000)

    CAS  Article  Google Scholar 

  18. Gubitz, A. K., Feng, W. & Dreyfuss, G. The SMN complex. Exp. Cell Res. 296, 51–56 (2004)

    CAS  Article  Google Scholar 

  19. Ranum, L. P. & Day, J. W. Myotonic dystrophy: RNA pathogenesis comes into focus. Am. J. Hum. Genet. 74, 793–804 (2004)

    CAS  Article  Google Scholar 

  20. Buj-Bello, A. et al. Muscle-specific alternative splicing of myotubularin-related 1 gene is impaired in DM1 muscle cells. Hum. Mol. Genet. 11, 2297–2307 (2002)

    CAS  Article  Google Scholar 

  21. Kanadia, R. N. et al. A muscleblind knockout model for myotonic dystrophy. Science 302, 1978–1980 (2003)

    ADS  CAS  Article  Google Scholar 

  22. Orrell, R. W. et al. Definitive molecular diagnosis of facioscapulohumeral dystrophy. Neurology 52, 1822–1826 (1999)

    CAS  Article  Google Scholar 

  23. Rogers, M., Sewry, C. A. & Upadhyaya, M. in FSHD Facioscapulohumeral Muscular Dystrophy: Clinical Medicine and Molecular Cell Biology (eds Upadhyaya, M. & Cooper, D. N.) 277–298 (BIOS Scientific Publishers, London and New York, 2004)

    Google Scholar 

  24. Lemmers, R. J. et al. D4F104S1 deletion in facioscapulohumeral muscular dystrophy: phenotype, size, and detection. Neurology 61, 178–183 (2003)

    CAS  Article  Google Scholar 

  25. Tupler, R. et al. Monosomy of distal 4q does not cause facioscapulohumeral muscular dystrophy. J. Med. Genet. 33, 366–370 (1996)

    CAS  Article  Google Scholar 

  26. Chaudhuri, T., Mukherjea, M., Sachdev, S., Randall, J. D. & Sarkar, S. Role of the fetal and α/β exons in the function of fast skeletal troponin T isoforms: correlation with altered Ca2+ regulation associated with development. J. Mol. Biol. 352, 58–71 (2005)

    CAS  Article  Google Scholar 

  27. Johnson, J. M. et al. Genome-wide survey of human alternative pre-mRNA splicing with exon junction microarrays. Science 302, 2141–2144 (2003)

    ADS  CAS  Article  Google Scholar 

  28. Dubowitz, V. Muscle Biopsy. A Practical Approach (Bailliere Tindall, London, 1985)

    Google Scholar 

Download references


We are indebted to all FSHD families and the FSH Society. We thank M. Mora for providing FSHD myoblasts; G. Di Giulio for performing the radiology; C. Ghigna, S. Jones, L. Castilla and members of the M.R.G. laboratory for helpful discussions; and S. Evans for assistance with preparing the manuscript. Space constraints have limited the amount of original work that we have been able to cover in this Letter. This work was supported by the Muscular Dystrophy Association (D.G.); Associazione Amici del Centro Dino Ferrari, Telethon Bank, Eurobiobank and R.F. 2002 Criobanca Automatizzata di Materiale Biologico (M.M.); Telethon (R.B.); and the Cariplo Fundation, NIH-NINDS, the Muscular Dystrophy Association, the Italian National Council for Research Progetto Genomica Funzionale, the Association Francaise contre les Myopaties, the Italian Ministry of Education, University, and Research, Legato Ferrari and Telethon (R.T). M.R.G. is an investigator of the Howard Hughes Medical Institute.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Rossella Tupler.

Ethics declarations

Competing interests

Drs Gabellini, Tupler and Green have filed U.S. patent application 20050054012, entitled “Methods of detecting and treating FSHD”.

Supplementary information

Supplementary Methods

Methods for RT-PCR analysis, real time RT–PCR, FRG1 transgene copy number determination, FRG1 transgene northern blotting, histological and histochemical analyses, analysis of sarcolemmal integrity, immunofluorescence analysis of FRG1, overexpression of ASF/SF2 in C2C12 cells.

Supplementary Figures

This file contains Supplementary Figures 1–9.

Supplementary Tables 1 and 2

Supplementary Table 1 details the histopathological and histochemical comparison of ten different skeletal muscles of FRG1 transgenic mice. Supplementary Table 2 details the comparison of the muscles affected and the degree of dystrophy between FSHD patients and FRG1 transgenic mice.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Gabellini, D., D'Antona, G., Moggio, M. et al. Facioscapulohumeral muscular dystrophy in mice overexpressing FRG1. Nature 439, 973–977 (2006).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing