Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands.
Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, Netherlands.
Eur J Hum Genet. 2018 Jan;26(1):94-106. doi: 10.1038/s41431-017-0015-0. Epub 2017 Nov 21.
Facioscapulohumeral muscular dystrophy is caused by incomplete repression of the transcription factor DUX4 in skeletal muscle as a consequence of D4Z4 macrosatellite repeat contraction in chromosome 4q35 (FSHD1) or variants in genes encoding D4Z4 chromatin repressors (FSHD2). A clinical hallmark of FSHD is variability in onset and progression suggesting the presence of disease modifiers. A well-known cis modifier is the polymorphic DUX4 polyadenylation signal (PAS) that defines FSHD permissive alleles: D4Z4 chromatin relaxation on non-permissive alleles which lack the DUX4-PAS cannot cause disease in the absence of stable DUX4 mRNA. We have explored the nature and relevance of a common variant of the major FSHD haplotype 4A161, which is defined by 1.6 kb size difference of the most distal D4Z4 repeat unit. While the short variant (4A161S) has been extensively studied, we demonstrate that the long variant (4A161L) is relatively common in the European population, is capable of expressing DUX4, but that DUX4 mRNA processing differs from 4A161S. While we do not find evidence for a difference in disease severity between FSHD carriers of an 4A161S or 4A161L allele, our study does uncover biallelic DUX4 expression in FSHD2 patients. Compared to control individuals, we observed an increased frequency of FSHD2 patients homozygous for disease permissive alleles, and who are thus capable of biallelic DUX4 expression, while SMCHD1 variant carriers with only one permissive allele were significantly more often asymptomatic. This suggests that biallelic DUX4 expression lowers the threshold for disease presentation and is a modifier for disease severity in FSHD2.
面肩肱型肌营养不良症是由于染色体 4q35 上的 D4Z4 大片段重复收缩导致的转录因子 DUX4 在骨骼肌中不完全抑制引起的（FSHD1），或者编码 D4Z4 染色质抑制剂的基因发生变异（FSHD2）。FSHD 的一个临床特征是发病和进展的可变性，提示存在疾病修饰因子。一个众所周知的顺式修饰因子是多态性的 DUX4 多聚腺苷酸化信号（PAS），它定义了 FSHD 允许等位基因：缺乏 DUX4-PAS 的非允许等位基因上的 D4Z4 染色质松弛不能在没有稳定的 DUX4 mRNA 的情况下导致疾病。我们已经探索了主要 FSHD 单倍型 4A161 的常见变体的性质和相关性，该变体由最远端 D4Z4 重复单元的 1.6kb 大小差异定义。虽然短变体（4A161S）已经被广泛研究，但我们证明长变体（4A161L）在欧洲人群中相对常见，能够表达 DUX4，但 DUX4 mRNA 处理与 4A161S 不同。虽然我们没有发现 FSHD 携带者的 4A161S 或 4A161L 等位基因在疾病严重程度上存在差异的证据，但我们的研究确实揭示了 FSHD2 患者的双等位基因 DUX4 表达。与对照个体相比，我们观察到 FSHD2 患者中纯合疾病允许等位基因的频率增加，因此能够进行双等位基因 DUX4 表达，而仅携带一个允许等位基因的 SMCHD1 变体携带者则显著无症状的频率更高。这表明双等位基因 DUX4 表达降低了疾病表现的阈值，并且是 FSHD2 疾病严重程度的修饰因子。
