Inter-individual differences in CpG methylation at D4Z4 correlate with clinical variability in FSHD1 and FSHD2
Inter-individual differences in CpG methylation at D4Z4 correlate with clinical variability in FSHD1 and FSHD2
复制标题
DOI：
10.1093/hmg/ddu486
复制
发表时间：
2015-02-01
影响因子：
3.5
通讯作者：
van der Maarel, Silvere M.
中科院分区：
文献类型：
--
作者：
Lemmers, Richard J. L. F.;Goeman, Jelle J.;van der Maarel, Silvere M.
面肩肱骨肌营养不良症（FSHD: MIM#158900）是一种常见的肌病，具有显著的但在很大程度上无法解释的临床间和家族内变异性。它是由第4号染色体上的D4Z4重复序列收缩到1-10个单位（FSHD1）或由D4Z4结合的染色质修饰子SMCHD1 （FSHD2）的突变引起的。这两种情况都会导致肌肉中D4Z4染色质结构的部分开放和D4Z4编码的聚腺苷化DUX4 mRNA的转录。我们在对照组、FSHD1和FSHD2个体中测量了D4Z4 CpG甲基化，发现D4Z4重复序列大小与甲基化显著相关。在对重复序列大小进行校正后，我们发现FSHD1和FSHD2个体临床严重程度的差异取决于对D4Z4低甲基化易感性的个体差异。在FSHD1中，对于D4Z4重复序列为1-6个单位的个体，其临床严重程度主要取决于D4Z4重复序列的大小。然而，在具有7 - 10个单位阵列的个体中，临床严重程度还取决于调节D4Z4甲基化的其他因素，因为受影响的个体（而非非渗透突变携带者）的D4Z4 CpG甲基化减少幅度大于基于致病性D4Z4重复序列大小的预期。在FSHD2中，这种表观遗传易感性取决于SMCHD1突变的性质以及D4Z4重复序列的大小，显性负突变比单倍不足突变更有害。因此，我们的研究确定了FSHD发病和疾病进展的显著变异性的表观遗传基础，这被认为是FSHD的临床标志。
Facioscapulohumeral muscular dystrophy (FSHD: MIM#158900) is a common myopathy with marked but largely unexplained clinical inter- and intra-familial variability. It is caused by contractions of the D4Z4 repeat array on chromosome 4 to 1-10 units (FSHD1), or by mutations in the D4Z4-binding chromatin modifier SMCHD1 (FSHD2). Both situations lead to a partial opening of the D4Z4 chromatin structure and transcription of D4Z4-encoded polyadenylated DUX4 mRNA in muscle. We measured D4Z4 CpG methylation in control, FSHD1 and FSHD2 individuals and found a significant correlation with the D4Z4 repeat array size. After correction for repeat array size, we show that the variability in clinical severity in FSHD1 and FSHD2 individuals is dependent on individual differences in susceptibility to D4Z4 hypomethylation. In FSHD1, for individuals with D4Z4 repeat arrays of 1-6 units, the clinical severity mainly depends on the size of the D4Z4 repeat. However, in individuals with arrays of 7 10 units, the clinical severity also depends on other factors that regulate D4Z4 methylation because affected individuals, but not non-penetrant mutation carriers, have a greater reduction of D4Z4 CpG methylation than can be expected based on the size of the pathogenic D4Z4 repeat array. In FSHD2, this epigenetic susceptibility depends on the nature of the SMCHD1 mutation in combination with D4Z4 repeat array size with dominant negative mutations being more deleterious than haploinsufficiency mutations. Our study thus identifies an epigenetic basis for the striking variability in onset and disease progression that is considered a clinical hallmark of FSHD.