PURPOSE OF REVIEW: In recent years, we have seen remarkable progress in our understanding of the disease mechanism underlying facioscapulohumeral muscular dystrophy (FSHD). The purpose of this review is to provide a comprehensive overview of our current understanding of the disease mechanism and to discuss the observations supporting the possibility of a developmental defect in this disorder. RECENT FINDINGS: In the majority of cases, FSHD is caused by contraction of the D4Z4 repeat array (FSHD1). This results in local chromatin relaxation and stable expression of the DUX4 retrogene in skeletal muscle, but only when a polymorphic DUX4 polyadenylation signal is present. In some cases (FSHD2), D4Z4 chromatin relaxation and stable DUX4 expression occur in the absence of D4Z4 array contraction. DUX4 is a germline transcription factor and its expression in skeletal muscle leads to activation of early stem cell and germline programs and transcriptional activation of retroelements. SUMMARY: Recent studies have provided a plausible disease mechanism for FSHD in which FSHD results from inappropriate expression of the germline transcription factor DUX4. The genes regulated by DUX4 suggest several mechanisms of muscle damage, and provide potential biomarkers and therapeutic targets that should be investigated in future studies.
PURPOSE OF REVIEW: In recent years, we have seen remarkable progress in our understanding of the disease mechanism underlying facioscapulohumeral muscular dystrophy (FSHD). The purpose of this review is to provide a comprehensive overview of our current understanding of the disease mechanism and to discuss the observations supporting the possibility of a developmental defect in this disorder. RECENT FINDINGS: In the majority of cases, FSHD is caused by contraction of the D4Z4 repeat array (FSHD1). This results in local chromatin relaxation and stable expression of the DUX4 retrogene in skeletal muscle, but only when a polymorphic DUX4 polyadenylation signal is present. In some cases (FSHD2), D4Z4 chromatin relaxation and stable DUX4 expression occur in the absence of D4Z4 array contraction. DUX4 is a germline transcription factor and its expression in skeletal muscle leads to activation of early stem cell and germline programs and transcriptional activation of retroelements. SUMMARY: Recent studies have provided a plausible disease mechanism for FSHD in which FSHD results from inappropriate expression of the germline transcription factor DUX4. The genes regulated by DUX4 suggest several mechanisms of muscle damage, and provide potential biomarkers and therapeutic targets that should be investigated in future studies.
Authors: Richard J F L Lemmers; Mariëlle Wohlgemuth; Rune R Frants; George W Padberg; Eva Morava; Silvere M van der Maarel Journal: Am J Hum Genet Date: 2004-10-04 Impact factor: 11.025
Authors: Linda N Geng; Zizhen Yao; Lauren Snider; Abraham P Fong; Jennifer N Cech; Janet M Young; Silvere M van der Maarel; Walter L Ruzzo; Robert C Gentleman; Rabi Tawil; Stephen J Tapscott Journal: Dev Cell Date: 2011-12-29 Impact factor: 12.270
Authors: Roberta Melchionna; Anna Di Carlo; Roberta De Mori; Claudia Cappuzzello; Laura Barberi; Antonio Musarò; Chiara Cencioni; Nobutaka Fujii; Hirokazu Tamamura; Marco Crescenzi; Maurizio C Capogrossi; Monica Napolitano; Antonia Germani Journal: Muscle Nerve Date: 2010-06 Impact factor: 3.217
Authors: J C de Greef; M Wohlgemuth; O A Chan; K B Hansson; D Smeets; R R Frants; C M Weemaes; G W Padberg; S M van der Maarel Journal: Neurology Date: 2007-09-04 Impact factor: 9.910
Authors: Sabrina Sacconi; Richard J L F Lemmers; Judit Balog; Patrick J van der Vliet; Pauline Lahaut; Merlijn P van Nieuwenhuizen; Kirsten R Straasheijm; Rashmie D Debipersad; Marianne Vos-Versteeg; Leonardo Salviati; Alberto Casarin; Elena Pegoraro; Rabi Tawil; Egbert Bakker; Stephen J Tapscott; Claude Desnuelle; Silvère M van der Maarel Journal: Am J Hum Genet Date: 2013-09-26 Impact factor: 11.025
Authors: Zizhen Yao; Lauren Snider; Judit Balog; Richard J L F Lemmers; Silvère M Van Der Maarel; Rabi Tawil; Stephen J Tapscott Journal: Hum Mol Genet Date: 2014-05-26 Impact factor: 6.150
Authors: Sabrina Sacconi; Audrey Briand-Suleau; Marilyn Gros; Christian Baudoin; Richard J L F Lemmers; Sophie Rondeau; Nadira Lagha; Pilvi Nigumann; Chiara Cambieri; Angela Puma; Françoise Chapon; Tanya Stojkovic; Christophe Vial; Françoise Bouhour; Michelangelo Cao; Elena Pegoraro; Philippe Petiot; Anthony Behin; Bras Marc; Bruno Eymard; Andoni Echaniz-Laguna; Pascal Laforet; Leonardo Salviati; Marc Jeanpierre; Gaël Cristofari; Silvère M van der Maarel Journal: Neurology Date: 2019-04-12 Impact factor: 9.910
Authors: Jong-Won Lim; Chao-Jen Wong; Zizhen Yao; Rabi Tawil; Silvère M van der Maarel; Daniel G Miller; Stephen J Tapscott; Galina N Filippova Journal: Hum Mol Genet Date: 2018-08-01 Impact factor: 6.150
Authors: Lukasz Ciszewski; Ngoc Lu-Nguyen; Alex Slater; Andrew Brennan; Huw E L Williams; George Dickson; Mark S Searle; Linda Popplewell Journal: Nucleic Acids Res Date: 2020-05-07 Impact factor: 16.971