title: Facioscapulohumeral dystrophy: the path to consensus on pathophysiology.
abstract: Although the pathophysiology of facioscapulohumeral dystrophy (FSHD) has been controversial over the last decades, progress in recent years has led to a model that incorporates these decades of findings and is gaining general acceptance in the FSHD research community. Here we review how the contributions from many labs over many years led to an understanding of a fundamentally new mechanism of human disease. FSHD is caused by inefficient repeat-mediated epigenetic repression of the D4Z4 macrosatellite repeat array on chromosome 4, resulting in the variegated expression of the DUX4 retrogene, encoding a double-homeobox transcription factor, in skeletal muscle. Normally expressed in the testis and epigenetically repressed in somatic tissues, DUX4 expression in skeletal muscle induces expression of many germline, stem cell, and other genes that might account for the pathophysiology of FSHD. Although some disagreements regarding the details of mechanisms remain in the field, the coalescing agreement on a central model of pathophysiology represents a pivot-point in FSHD research, transitioning the field from discovery-oriented studies to translational studies aimed at developing therapies based on a sound model of disease pathophysiology.
authors.affiliation: Department of Neurology, University of Rochester, Rochester, NY 14642, USA ; Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA.
authors.forename: Rabi
authors.initials: R
authors.lastname: Tawil
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands ; Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA.
authors.forename: Silvère M
authors.initials: SM
authors.lastname: van der Maarel
authors.affiliation: Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA ; Department of Neurology, University of Washington, Seattle, WA 98105, USA ; Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Tapscott
keywords: DUX4; Epigenetic; Facioscapulohumeral muscular dystrophy; SMCHD1; Tandem repeat sequences