Facioscapulohumeral muscular dystrophy and DUX4: breaking the silence.

Department of Human Genetics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, Netherlands.
Trends in Molecular Medicine (Impact Factor: 10.11). 05/2011; 17(5):252-8. DOI: 10.1016/j.molmed.2011.01.001
Source: PubMed

ABSTRACT Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) has an unusual pathogenic mechanism. FSHD is caused by deletion of a subset of D4Z4 macrosatellite repeat units in the subtelomere of chromosome 4q. Recent studies provide compelling evidence that a retrotransposed gene in the D4Z4 repeat, DUX4, is expressed in the human germline and then epigenetically silenced in somatic tissues. In FSHD, the combination of inefficient chromatin silencing of the D4Z4 repeat and polymorphisms on the FSHD-permissive alleles that stabilize the DUX4 mRNAs emanating from the repeat result in inappropriate DUX4 protein expression in muscle cells. FSHD is thereby the first example of a human disease caused by the inefficient repression of a retrogene in a macrosatellite repeat array.


Available from: Rabi Tawil, Jun 10, 2015
  • [Show abstract] [Hide abstract]
    ABSTRACT: Facioscapulohumeral dystrophy (FSHD) is a unique and complex genetic disease that is not entirely solved. Recent advances in the field have led to a consensus genetic premise for the disorder, enabling researchers to now pursue the design of preclinical models. In this review we explore all available FSHD models (DUX4-dependent and -independent) for their utility in therapeutic discovery and potential to yield novel disease insights. Owing to the complex nature of FSHD, there is currently no single model that accurately recapitulates the genetic and pathophysiological spectrum of the disorder. Existing models emphasize only specific aspects of the disease, highlighting the need for more collaborative research and novel paradigms to advance the translational research space of FSHD. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Trends in Molecular Medicine 03/2015; 21(5). DOI:10.1016/j.molmed.2015.02.011 · 10.11 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: A depth-ranging sensor (Kinect) based upper extremity motion analysis system was applied to determine the spectrum of reachable workspace encountered in facioscapulohumeral muscular dystrophy (FSHD).Methods: Reachable workspaces were obtained from 22 individuals with FSHD and 24 age- and height-matched healthy controls. To allow comparison, total and quadrant reachable workspace relative surface areas (RSA) were obtained by normalizing the acquired reachable workspace by each individual's arm length.Results: Significantly contracted reachable workspace and reduced RSAs were noted for the FSHD cohort compared to controls (0.473±0.188 vs. 0.747±0.082; P<0.0001). With worsening upper extremity function as categorized by the FSHD evaluation subscale II+III, the upper quadrant RSAs decreased progressively, while the lower quadrant RSAs were relatively preserved. There were no side-to-side differences in reachable workspace based on hand-dominance.Discussion: This study demonstrates the feasibility and potential of using an innovative Kinect-based reachable workspace outcome measure in FSHD. © 2014 Wiley Periodicals, Inc.
    Muscle & Nerve 02/2015; 51(2). DOI:10.1002/mus.24287 · 2.31 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Facioscapulohumeral muscular dystrophy (FSHD) is a common type of adult muscular dystrophy and is divided into types 1 and 2 based on genetic mutation. Clinically, both FSHD types often show asymmetric and progressive muscle weakness affecting initially the face, shoulder, and arms followed by the distal then proximal lower extremities. Approximately 95% of patients, termed FSHD1, have a deletion of a key number of repetitive elements on chromosome 4q35. The remaining 5%, termed FSHD2, have no deletion on chromosome 4q35. Nevertheless, both types share a common downstream mechanism, making it possible for future disease-directed therapies to be effective for both FSHD types.
    Neurologic Clinics 08/2014; DOI:10.1016/j.ncl.2014.04.003 · 1.61 Impact Factor