Department of Neurology, University of Rochester Medical Center, Rochester, New York, USA.
Curr Opin Neurol. 2011 Oct;24(5):423-8. doi: 10.1097/WCO.0b013e32834959af.
Recent advances have provided a model for understanding the underlying molecular genetic changes in facioscapulohumeral muscular dystrophy (FSHD). This review will highlight our current understanding and future research directions.
FSHD typically results from contraction of a critical number of D4Z4 repeats in a macrosatellite repeat array on chromosome 4q35. Contraction leads to loss of DNA methylation and heterochromatin markers in the 4q35 D4Z4 region, resulting in relaxation of the chromatin structure and release of DUX4 repression. DUX4, a retrogene contained in the D4Z4 repeats, is normally epigenetically silenced in somatic cells. Stable expression of DUX4, however, can only occur in the presence of a permissive genetic background, which contains a polyadenylation signal sequence that stabilizes DUX4 mRNA. Expression of DUX4 mRNA and protein occurs at low frequency but in high abundance in FSHD myotube nuclei. DUX4 expression in transfection studies induces apoptosis and interferes with myogenesis.
FSHD results from a unique combination of genetic and epigenetic changes on 4q35 leading to release of repression of DUX4, causing disease in a toxic gain-of-function manner. Questions remain regarding the normal function of DUX4 and how expression of DUX4 in somatic cells leads to FSHD.
最近的进展为理解面肩肱型肌营养不良症（FSHD）的潜在分子遗传变化提供了一个模型。这篇综述将重点介绍我们目前的理解和未来的研究方向。
FSHD 通常是由于 4 号染色体 q35 上的一个大片段重复阵列中的 D4Z4 重复收缩到一个关键数量而导致的。收缩导致 4q35 D4Z4 区域的 DNA 甲基化和异染色质标记丢失，导致染色质结构松弛和 DUX4 抑制物的释放。DUX4 是 D4Z4 重复中的一个返座基因，通常在体细胞中被表观遗传沉默。然而，只有在存在允许的遗传背景下，稳定表达 DUX4 才可能发生，这种背景包含一个稳定 DUX4 mRNA 的多聚腺苷酸化信号序列。在 FSHD 肌管核中，低频率但高丰度地表达 DUX4 mRNA 和蛋白。转染研究中的 DUX4 表达诱导细胞凋亡并干扰肌生成。
FSHD 是由 4q35 上的遗传和表观遗传变化的独特组合导致的，导致 DUX4 抑制物的释放，以毒性获得功能的方式引起疾病。关于 DUX4 的正常功能以及 DUX4 在体细胞中的表达如何导致 FSHD 的问题仍然存在。
