Journal Article

Facioscapulohumeral muscular dystrophy family studies of <i>DUX4</i> expression: evidence for disease modifiers and a quantitative model of pathogenesis

Takako Iida Jones, Jennifer C. J. Chen, Fedik Rahimov, Sachiko Homma, Patricia Arashiro, Mary Lou Beermann, Oliver D. King, Jeffrey B. Miller, Louis M. Kunkel, Charles P. Emerson, Kathryn R. Wagner and Peter L. Jones

in Human Molecular Genetics

Volume 21, issue 20, pages 4419-4430
Published in print October 2012 | ISSN: 0964-6906
Published online July 2012 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/dds284
Facioscapulohumeral muscular dystrophy family studies of DUX4 expression: evidence for disease modifiers and a quantitative model of pathogenesis

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Facioscapulohumeral muscular dystrophy (FSHD), the most prevalent myopathy afflicting both children and adults, is predominantly associated with contractions in the 4q35-localized macrosatellite D4Z4 repeat array. Recent studies have proposed that FSHD pathology is caused by the misexpression of the DUX4 (double homeobox 4) gene resulting in production of a pathogenic protein, DUX4-FL, which has been detected in FSHD, but not in unaffected control myogenic cells and muscle tissue. Here, we report the analysis of DUX4 mRNA and protein expression in a much larger collection of myogenic cells and muscle biopsies derived from biceps and deltoid muscles of FSHD affected subjects and their unaffected first-degree relatives. We confirmed that stable DUX4-fl mRNA and protein were expressed in myogenic cells and muscle tissues derived from FSHD affected subjects, including several genetically diagnosed adult FSHD subjects yet to show clinical manifestations of the disease in the assayed muscles. In addition, we report DUX4-fl mRNA and protein expression in muscle biopsies and myogenic cells from genetically unaffected relatives of the FSHD subjects, although at a significantly lower frequency. These results establish that DUX4-fl expression per se is not sufficient for FSHD muscle pathology and indicate that quantitative modifiers of DUX4-fl expression and/or function and family genetic background are determinants of FSHD muscle disease progression.

Journal Article.  8129 words.  Illustrated.

Subjects: Genetics and Genomics

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