What causes facioscapulohumeral dystrophy (FSHD)?

Updated: Mar 19, 2019
  • Author: Naganand Sripathi, MD; Chief Editor: Amy Kao, MD  more...
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The actual genetic defect in FSHD is unknown. Possible disease mechanisms include the following:

  • Position variegation effect on a proximal candidate gene or genes

  • Direct and indirect evidence points to epigenetic modifications in the DNA. A local deficit of a repressor complex due to the contraction of D4Z4 may cause inappropriate expression of genes. This may account for upregulation of FRG2, FRG1, and ANT1 in FSHD muscle.

  • The most common modification of mammalian DNA is cytosine methylation that is necessary for many regulatory processes. D4Z4 was found to be hypomethylated in FSHD.

  • Myoblasts from patients with FSHD also demonstrate increased susceptibility to oxidative stress.

  • Misexpression of FRG1 (FSHD region gene 1) may lead to the development of FSHD. Knockdown of FRG1 in Xenopus led to the decreased angiogenesis and reduced expression of DAB2 (angiogenic regulator). Of patients with FSHD, 50-75% exhibit retinal vasculopathy and increased expression of vascular or endothelial-related FRG1 transcripts in the muscle. Thus FRG1 may be at least crucial for angiogenesis.

  • Deletion of D4Z4 macrosatellites results in aberrant gene expression. DUX4 transcript from the last D4Z4 (most telomeric) unit generates small si/miRNA-sized fragments; uncapped, polyadenylated 3-prime fragments encoding C-terminal portion of DUX4; capped and polyadenylated mRNAs containing the double-homeobox domain of DUX4, but splice-out the C-terminal polypeptide. C-terminal polypeptide produced by transfection studies inhibits myogenesis. [3]

  • DUX4 is a retrogene contained within D4Z4 repeats and is normally epigenetically silenced in somatic cells. D4Z4 contraction leads to loss of DNA methylation and heterochromatin markers in D4Z4 region, resulting in relaxation of chromatin structure and release DUX4 repression. [4]

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