Facioscapulohumeral muscular dystrophy family studies of DUX4 expression: evidence for disease modifiers and a quantitative model of pathogenesis
Facioscapulohumeral muscular dystrophy family studies of DUX4 expression: evidence for disease modifiers and a quantitative model of pathogenesis
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DOI：
10.1093/hmg/dds284
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发表时间：
2012-10-15
影响因子：
3.5
通讯作者：
Jones, Peter L.
中科院分区：
文献类型：
--
作者：
Jones, Takako Iida;Chen, Jennifer C. J.;Jones, Peter L.
面肩肱型肌营养不良症（FSHD）是一种常见的儿童和成人肌肉疾病，主要与4 q35定位的大卫星D4 Z4重复序列的收缩有关。最近的研究表明，FSHD病理是由DUX 4（双同源框4）基因的错误表达引起的，导致产生致病蛋白DUX 4-FL，其已在FSHD中检测到，但在未受影响的对照生肌细胞和肌肉组织中未检测到。在这里，我们报告了DUX 4 mRNA和蛋白表达的分析，在一个更大的收集肌源性细胞和肌肉活检来自二头肌和三角肌的FSHD受影响的科目和他们的未受影响的一级亲属。我们证实了稳定的DUX 4-fl mRNA和蛋白质在源自FSHD受影响的受试者的肌源性细胞和肌肉组织中表达，所述受试者包括尚未在所测定的肌肉中显示出疾病的临床表现的几种遗传诊断的成年FSHD受试者。此外，我们报告DUX 4-fl mRNA和蛋白质表达的肌肉活检和肌原性细胞从遗传上未受影响的亲属的FSHD的主题，虽然在一个显着较低的频率。这些结果证实DUX 4-fl表达本身对于FSHD肌肉病理学是不够的，并且表明DUX 4-fl表达和/或功能的定量修饰剂和家族遗传背景是FSHD肌肉疾病进展的决定因素。
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.