This report describes facioscapulohumeral muscular dystrophy 1 (FSHD1); FSHD1 exhibits autosomal dominant inheritance. Most cases of FSHD are associated with contraction of a D4Z4 repeat region on chromosome 4. A copy of the DUX4 gene, a double-homeobox-containing transcription factor, lies within each repeat unit, but it is postulated that only the distal copy is functional. Contraction of the D4Z4 repeat region appears to result in epigenetic chromatin relaxation and overexpression of the DUX4 gene. Although there are distantly related transcription factor genes, no genes orthologous to DUX4 have been identified outside of primates. See also the human disease model report for FSHD, FRG1-related (FBhh0000651).
A UAS construct of a tagged wild-type human Hsap\DUX4 gene that expresses the full-length protein isoform has been introduced into flies. Ubiquitous expression results in lethality; later expression restricted to muscle also results in lethality. Expression in the adult eye is semi-lethal (completely male-lethal); female escapers exhibit severe eye phenotypes. This system may be amenable to genetic screening for enhancers and suppressors of DUX4 function.
[updated May 2025 by FlyBase; FBrf0222196]
[FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY 1; FSHD1](https://omim.org/entry/158900)
[FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY 1; FSHD1](https://omim.org/entry/158900)
Facioscapulohumeral muscular dystrophy (FSHD) typically presents before age 20 years with weakness of the facial muscles and the stabilizers of the scapula or the dorsiflexors of the foot. Weakness is slowly progressive and severity is highly variable; approximately 20% of affected individuals eventually require a wheelchair. Life expectancy is not shortened. [Gene Reviews, Facioscapulohumeral Muscular Dystrophy (Lemmers, et al., 2014)]
Facioscapulohumeral muscular dystrophy is the third most common hereditary disease of muscle after Duchenne (DMD) and myotonic dystrophy. It is a highly variable disorder with weakness appearing from infancy to late life but typically in the second decade. In general, the disease initially involves the face and the scapulae followed by the foot dorsiflexors and the hip girdles, with striking asymmetry of muscle involvement from side to side (Tawil et al., 1998; pubmed:9506542). [from MIM:158900; 2017.10.31]
FSHD is likely caused by overexpression of the double homeobox-containing gene DUX4 in muscle cells. Derepression of DUX4 is postulated to be caused by chromatin relaxation effected by different epigenetic mechanisms, including reduction in the number of encompassing D4Z4 repeat units or mutation in a chromatin modifier gene. DUX4 lies in the macrosatellite repeat D4Z4, which has a length between 11 and 100 repeat units in unaffected individuals; approximately 95% of individuals with FSHD have between one and ten D4Z4 repeat units. [Gene Reviews, Facioscapulohumeral Muscular Dystrophy (Lemmers, et al., 2014)]
FSHD exhibits autosomal dominant inheritance. [Gene Cards, DUX4; 2017.10.31]
Facioscapulohumeral muscular dystrophy-1 (FSHD1) is associated with contraction of the D4Z4 macrosatellite repeat in the subtelomeric region of chromosome 4q35. [from MIM:158900; 2017.10.31]
A copy of DUX4 is found within each of up to 100 copies of the D4Z4 macrosatellite repeat in the subtelomeric region of chromosome 4q. Only the last repeat appears to encode a functional DUX4 transcript with a polyadenylation site that lies telomeric to and outside of the D4Z4 repeat region (summary by Snider et al., 2010; pubmed:21060811). [from MIM:606009; 2017.10.31]
DUX4-FL (full-length isoform) is highly cytotoxic when expressed in vertebrate somatic cells in culture or during vertebrate embryonic development (FBrf0231179 and references cited therein).
DUX4 encodes a transcription factor expressed in multiple tissues including testis and pluripotent stem cells; in FSHD, increased levels of DUX4 lead to aberrant regulation of target genes (FBrf0231179 and references cited therein).
The DUX4 gene encodes at least two different protein isoforms generated through alternative mRNA splicing: a non-pathogenic 'short' form of unknown function expressed at low levels in healthy somatic cells and a longer 'full-length' form (DUX4-FL) that is expressed in the male germ line and can be highly cytotoxic when expressed in somatic cells. Only expression of the DUX4-FL isoform is linked to FSHD (FBrf0231179 and references cited therein).
No gene orthologous to human DUX4 has been identified in Drosophila, but some paired homeobox transcription factors have regions of similarity.
