Facioscapulohumeral Muscular Dystrophy

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is a common, dominantly inherited, muscle disease with a distinctive clinical presentation and a wide spectrum of disease severity. In greater than 95% of individuals with FSHD, the genetic defect is a loss of a critical number of D4Z4 macrosatellite repeats on chromosome 4q35. However, D4Z4 contractions are only pathogenic on specific, permissive chromosomal backgrounds. Recent evidence demonstrates that this permissive background facilitates the stable transcription of DUX4, a retrogene sequence within D4Z4 that codes for a double homeodomain protein of unknown function. These findings implicate DUX4 in the pathophysiology of FSHD and for the first time, offer a target for therapeutic development in FSHD.

Key Concepts:

  • Epigenetic modifications can lead to gene derepression.

  • FSHD results from reactivation of a retrogene.

Keywords: FSHD; facioscapulohumeral muscular dystrophy; muscular dystrophy; chromosome 4; myostatin; DUX4

Figure 1.

Characteristic changes in shoulders of patients with FSHD: (a) Straight clavicles and axillary creases (indicative of pectoral atrophy); (b) Asymmetric winging of the scapula; (c) inability to raise arm above shoulder level secondary to weakness of periscapular muscles and (d) improved arm range of motion when scpula is manually stabilised. Reproduced with permission from Tawil and van der Maarel ().

Figure 2.

Two FSHD molecular mechanisms: (a) FSHD1 results from a loss of a critical number of D4Z4 repeats to between 1 and 10 repeats associated with chromatin relaxation and (b) FSHD2 results from chromatin relaxation not associated with loss of D4Z4 repeats. In both instances, the chromatin relaxation creates a change in the transcriptional landscape of D4Z4, including expression of DUX4. However, only the transcript from the last D4Z4 unit is stabilised by utilisation of a unique third exon in the distal pLAM1 sequence containing a polyadenylation signal.

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Further Reading

Dmitriev P, Lipinski M and Vassetzky Y (2009) Pearls in the junk: dissecting the molecular pathogenesis of facioscapulohumeral muscular dystrophy. Neuromuscular Disorder 19(1): 17–20.

Upadhaya M and Cooper D (eds) (2004) Facioscapulohumeral muscular dystrophy (FSHD): clinical medicine and molecular cell biology. Abingdon, Oxon, UK: Garland Science/BIOS Scientific publishers.

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How to Cite close
Rabi, Tawil, and Van der Maarel, Silvere(Apr 2011) Facioscapulohumeral Muscular Dystrophy. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021439]