Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands.
Curr Opin Neurol. 2012 Oct;25(5):614-20. doi: 10.1097/WCO.0b013e328357f22d.
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.
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.
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.
综述目的：近年来，我们对脑-面-肩-肱型肌营养不良症（FSHD）的疾病机制有了显著的认识进展。本文的综述目的是全面概述我们目前对疾病机制的理解，并讨论支持该疾病存在发育缺陷可能性的观察结果。
最新发现：在大多数情况下，FSHD 是由 D4Z4 重复序列簇的收缩引起的（FSHD1）。这导致局部染色质松弛和骨骼肌中 DUX4 返座基因的稳定表达，但只有在存在多态性 DUX4 聚腺苷酸化信号时才会发生。在某些情况下（FSHD2），即使不存在 D4Z4 阵列收缩，D4Z4 染色质松弛和稳定的 DUX4 表达也会发生。DUX4 是一种生殖系转录因子，其在骨骼肌中的表达导致早期干细胞和生殖系程序的激活，以及返座元件的转录激活。
总结：最近的研究为 FSHD 提供了一个合理的疾病机制，即 FSHD 是由生殖系转录因子 DUX4 的异常表达引起的。DUX4 调控的基因提示了几种肌肉损伤的机制，并为未来的研究提供了潜在的生物标志物和治疗靶点。
