Division of Molecular Genetics & Epigenetics, Department of Biomolecular Sciences, Saga University Faculty of Medicine, Saga, Japan
Department of Pediatrics, Amakusa Medical Center, Amakusa, Japan.
J Med Genet. 2021 Jun;58(6):422-425. doi: 10.1136/jmedgenet-2020-106907. Epub 2020 May 23.
Silver-Russell syndrome (SRS) is a representative imprinting disorder. A major cause is the loss of methylation (LOM) of imprinting control region 1 (ICR1) within the domain. ICR1 is a gametic differentially methylated region (DMR) consisting of two repeat blocks, with each block including three CTCF target sites (CTSs). ICR1-LOM on the paternal allele allows CTCF to bind to CTSs, resulting in repression on the paternal allele and biallelic expression of We analysed 10 differentially methylated sites (DMSs) (ie, seven CTSs and three somatic DMRs within the domain, including two -DMRs and the -promoter) in five SRS patients with ICR1-LOM. Four patients showed consistent hypomethylation at all DMSs; however, one exhibited a peculiar LOM pattern, showing LOM at the centromeric region of the / domain but normal methylation at the telomeric region. This raised important points: there may be a separate regulation of DNA methylation for the two repeat blocks within ICR1; there is independent control of somatic DMRs under each repeat block; sufficient repression to cause SRS phenotypes occurs by LOM only in the centromeric block; and the need for simultaneous methylation analysis of several DMSs in both blocks for a correct molecular diagnosis.
银-罗素综合征（SRS）是一种代表性的印迹疾病障碍。主要原因是印迹控制区 1（ICR1）在 域内的甲基化丢失（LOM）。ICR1 是一个配子差异甲基化区域（DMR），由两个重复块组成，每个块包含三个 CTCF 靶位点（CTSs）。父本等位基因上的 ICR1-LOM 允许 CTCF 结合到 CTSs，导致父本等位基因上的 抑制和 的双等位基因表达。我们分析了 10 个差异甲基化位点（DMS）（即， 域内的七个 CTSs 和三个体细胞 DMR，包括两个 -DMR 和 -启动子）在 5 个具有 ICR1-LOM 的 SRS 患者中。四个患者在所有 DMS 上均表现出一致的低甲基化；然而，一个患者表现出特殊的 LOM 模式，在 / 域的着丝粒区域表现出 LOM，但在端粒区域表现出正常甲基化。这提出了重要的观点：ICR1 内的两个重复块的 DNA 甲基化可能存在单独的调节；每个重复块下的体细胞 DMR 具有独立的控制；仅在着丝粒块中发生 LOM 就足以引起 SRS 表型；并且需要同时分析两个块中的多个 DMS 以进行正确的分子诊断。
