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FRG2, an FSHD candidate gene, is transcriptionally upregulated in differentiating primary myoblast cultures of FSHD patients
  1. T Rijkers1,*,
  2. G Deidda1,*,
  3. S van Koningsbruggen1,
  4. M van Geel2,
  5. R J L F Lemmers1,
  6. J C T van Deutekom1,
  7. D Figlewicz3,,
  8. J E Hewitt4,
  9. G W Padberg5,
  10. R R Frants1,
  11. S M van der Maarel1
  1. 1Department of Human Genetics, Center for Human and Clinical Genetics, Leiden University Medical Center, Wassenaarseweg 72, 2333 AL Leiden, The Netherlands
  2. 2Department of Dermatology, Academic Hospital Maastricht, Maastricht, The Netherlands
  3. 3Departments of Neurology and Neurobiology and Anatomy, University of Rochester Medical Center, Rochester, NY, USA
  4. 4Institute of Genetics, Queen’s Medical Center, University of Nottingham, N97 2UH, Nottingham, UK
  5. 5Department of Neurology, University Hospital Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands
  1. Correspondence to:
 Dr S M van der Maarel
 Department of Human Genetics, Center for Human and Clinical Genetics, Leiden University Medical Center, Wassenaarseweg 72, 2333 AL Leiden, The Netherlands;


Background: Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) is associated with partial deletion of the subtelomeric D4Z4 repeat array on chromosome 4qter. This chromosomal rearrangement may result in regional chromatin relaxation and transcriptional deregulation of genes nearby.

Methods and results: Here we describe the isolation and characterisation of FRG2, a member of a chromosomally dispersed gene family, mapping only 37 kb proximal to the D4Z4 repeat array. Homology and motif searches yielded no clues to the function of the predicted protein. FRG2 expression is undetectable in all tissues tested except for differentiating myoblasts of FSHD patients, which display low, yet distinct levels of FRG2 expression, partly from chromosome 4 but predominantly originating from its homologue on chromosome 10. However, in non-FSHD myopathy patients only distantly related FRG2 homologues are transcribed, while differentiating myoblasts from healthy controls fail to express any member of this gene family. Moreover, fibroblasts of FSHD patients and control individuals undergoing forced Ad5-MyoD mediated myogenesis show expression of FRG2 mainly originating from chromosome 10. Luciferase reporter assays show that the FRG2 promoter region can direct high levels of expression but is inhibited by increasing numbers of D4Z4 repeat units. Transient transfection experiments with FRG2 fusion-protein constructs reveal nuclear localisation and apparently FRG2 overexpression causes a wide range of morphological changes.

Conclusion: The localisation of FRG2 genes close to the D4Z4 repeats on chromosome 4 and 10, their transcriptional upregulation specifically in FSHD myoblast cultures, potential involvement in myogenesis, and promoter properties qualify FRG2 as an attractive candidate for FSHD pathogenesis.

  • DSM, desmin storage myopathy
  • EGFP, enhanced green fluorescent protein
  • FISH, fluorescence in situ hybridisation
  • FSHD, facioscapulohumeral muscular dystrophy
  • HS, horse serum
  • NLS, nuclear localisation signals
  • ORF, open reading frame
  • PROMM, proximal myotonic myopathy
  • VSV-G, vesicular stomatitis virus glycoprotein
  • FRG2
  • FSHD
  • muscle
  • myoblasts

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  • This study was supported by the FSH Society Inc. (Marjorie Bronfman fellowship grants to SMVDM and TR), the Prinses Beatrix Fonds, the Netherlands Organization for Scientific Research (NWO), the Muscular Dystrophy Association, and the Dutch FSHD Foundation.

  • Conflict of interest: none declared.

  • * Current address: Institute of Cell Biology, CNR, 43 Viale Marx, 00137 Rome, Italy.

  • Current address: Department of Neurology, University of Michigan, Ann Arbor, MI, USA.

  • The FRG2 cDNA sequence of chromosome 4 has been submitted to the GenBank database. The accession number is AY714545.

  • The cDNA sequence (5’ UTR and CRF) of the FRG2 homologue on chromosome 10 has also been submitted to the GenBank database. The accession number is AY744466.