Tawil Rabi
Department of Neurology, University of Rochester Medical Center, Rochester, NY, United States.
Handb Clin Neurol. 2018;148:541-548. doi: 10.1016/B978-0-444-64076-5.00035-1.
Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common forms of muscular dystrophy with a distinctive pattern of skeletal muscle weakness and a wide spectrum of disease severity. The pathophysiologic consequences of the genetic lesion, the loss of a critical number of macrosatellite repeats (D4Z4) in the subtelomeric region of chromosome 4q35, remained unexplained for almost two decades. Recent studies demonstrate that contraction in the number of D4Z4 repeats results in chromatin relaxation and transcriptional de-repression of DUX4, a gene normally expressed only in the germline. In about 5% of individuals with phenotypic FSHD, there is no contraction in the D4Z4 repeats and yet similar chromatin changes are present, resulting in the inappropriate expression of the DUX4 gene. The chromatin changes in this form of FSHD (FSHD2) are the result, in most cases, of mutations in SMCHD1, a gene on chromosome 18 involved in chromatin regulation. The recent identification of aberrant activation of DUX4 transcription in FSHD as the root cause of FSHD now allows for a targeted approach to therapeutic development.
面肩肱型肌营养不良症（FSHD）是最常见的肌营养不良症形式之一，具有独特的骨骼肌无力模式和广泛的疾病严重程度谱。在近二十年的时间里，4号染色体长臂35区（4q35）亚端粒区域关键数量的大卫星重复序列（D4Z4）缺失这一基因损伤的病理生理后果一直未得到解释。最近的研究表明，D4Z4重复序列数量的减少会导致染色质松弛以及DUX4基因转录去抑制，该基因通常仅在生殖细胞系中表达。在约5%具有FSHD表型的个体中，D4Z4重复序列没有减少，但仍存在类似的染色质变化，导致DUX4基因异常表达。这种形式的FSHD（FSHD2）中的染色质变化在大多数情况下是由SMCHD1基因突变引起的，SMCHD1是18号染色体上一个参与染色质调控的基因。最近确定FSHD中DUX4转录异常激活是FSHD的根本原因，这使得治疗开发有了针对性的方法。
