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FRG1P is localised in the nucleolus, Cajal bodies, and speckles
  1. S van Koningsbruggen1,
  2. R W Dirks2,
  3. A M Mommaas3,
  4. J J Onderwater3,
  5. G Deidda4,
  6. G W Padberg5,
  7. R R Frants1,
  8. S M van der Maarel1
  1. 1Department of Human Genetics, Leiden University Medical Center, Netherlands
  2. 2Department of Molecular Cell Biology, Leiden University Medical Center, Netherlands
  3. 3Centre for Electron Microscopy, Leiden University Medical Center, Netherlands
  4. 4Institute of Cell Biology, CNR, Rome, Italy
  5. 5Department of Neurology, University Medical Center Nijmegen, Netherlands
  1. Correspondence to:
 S M van der Maarel
 Leiden University Medical Center, MGC-Department of Human Genetics, Wassenaarseweg 72, 2333 AL Leiden, Netherlands; maarellumc.nl

https://doi.org/10.1136/jmg.2003.012781

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    The highly conserved facioscapulohumeral muscular dystrophy (FSHD) region gene 1 (FRG1) was initially cloned as candidate gene of unknown function for FSHD. To explore the biological function of the FRG1 protein (FRG1P), we studied its cellular localisation in untransfected and FRG1 transfected cell lines. In interphase cells, FRG1P is localised in the dense structures of the nucleolus, in Cajal bodies, and in 60–80% of cells in nuclear speckles. A time course study revealed that FRG1P accumulates in nuclear speckles before its appearance in nucleoli, whereas the localisation in Cajal bodies remains unchanged, as does the localisation of NHPX protein. In accordance with the presence of FRG1P in these nuclear structures, transcription inhibition experiments showed an effect of RNA polymerases I and II on the localisation of FRG1P. Finally, by deletion of the predicted nuclear localisation signals of FRG1P, we demonstrated that both signals are necessary for this subnuclear localisation.

    FRG1P is an attractive candidate for the pathogenesis of FSHD because of its high evolutionary conservation; its transcriptional deregulation in FSHD; and its colocalisation with proteins that are defective in the neuromuscular disorders oculopharyngeal muscular dystrophy (OPMD) and spinal muscular atrophy (SMA).

    FRG1 (FSHD Region Gene 1, accession number L76159) was isolated as the first candidate gene for the autosomal dominant myopathy, facioscapulohumeral muscular dystrophy, in 1996.1 FSHD is primarily characterised by progressive weakness and atrophy of the facial, upper arm, and shoulder muscles.2 The FSHD locus on 4q35 contains a polymorphic repeat array consisting of 3.3 kb repeated elements (D4Z4). In control individuals, this array may vary between 11–100 units, whereas FSHD patients carry 1–10 units on one of their chromosomes 4, owing to the deletion of an integral number of D4Z4 units.3 It is becoming increasingly evident that FSHD is caused by a local chromatin alteration, …

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