Hypomethylation of a centromeric block of ICR1 is sufficient to cause Silver-Russell syndrome.
Hypomethylation of a centromeric block of ICR1 is sufficient to cause Silver-Russell syndrome.
复制标题
着丝粒ICR1的低甲基化足以引起银罗素综合征。
DOI：
10.1136/jmedgenet-2020-106907
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发表时间：
2021-06
影响因子：
4
通讯作者：
Soejima H
中科院分区：
文献类型：
--
作者：
Higashimoto K;Watanabe H;Tanoue Y;Tonoki H;Tokutomi T;Hara S;Yatsuki H;Soejima H
Silver-Russell综合征(SRS)是一种典型的印迹障碍。一个主要原因是IGF2/H19结构域内印迹控制区1(ICR1)的甲基化(LOM)丢失。ICR1是一个配子差异甲基化区域(DMR)，由两个重复区块组成，每个区块包括三个CTCF靶点(CTS)。父本等位基因上的ICR1-LOM允许CTCF与CTS结合，导致IGF2抑制父本等位基因和H19的双等位基因表达。我们分析了5例患有ICR1-LOM的SRS患者的10个差异甲基化位点(DMS)(即7个CTS和3个IGF2/H19结构域中的体细胞DMR，包括2个IGF2-DMR和H19-启动子)。4名患者在所有DMS中均表现出一致的低甲基化；然而，1名患者表现出一种特殊的LOM模式，在IGF2/H19结构域的着丝粒区域显示LOM，但在端粒区域正常甲基化。这提出了重要的几点：ICR1内两个重复区块的DNA甲基化可能有一个单独的调节；每个重复区块下的体细胞DMRS有独立的控制；只有着丝粒区块中有足够的IGF2抑制才能引起SRS表型；为了正确的分子诊断，需要在两个区块中同时对几个DMS进行甲基化分析。
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 IGF2/H19 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 IGF2 repression on the paternal allele and biallelic expression of H19. We analysed 10 differentially methylated sites (DMSs) (ie, seven CTSs and three somatic DMRs within the IGF2/H19 domain, including two IGF2-DMRs and the H19-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 IGF2/H19 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 IGF2 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.
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影响因子：
5.7
作者：
Hidaka H;Higashimoto K;Aoki S;Mishima H;Hayashida C;Maeda T;Koga Y;Yatsuki H;Joh K;Noshiro H;Iwakiri R;Kawaguchi A;Yoshiura KI;Fujimoto K;Soejima H
通讯作者：
Soejima H
影响因子：
5.7
作者：
Sparago, Angela;Cerrato, Flavia;Riccio, Andrea
通讯作者：
Riccio, Andrea
影响因子：
11.8
作者：
Li, Xiajun;Ito, Mitsuteru;Zhou, Fen;Youngson, Neil;Zuo, Xiaopan;Leder, Philip;Ferguson-Smith, Anne C.
通讯作者：
Ferguson-Smith, Anne C.
影响因子：
16
作者：
Quenneville S;Verde G;Corsinotti A;Kapopoulou A;Jakobsson J;Offner S;Baglivo I;Pedone PV;Grimaldi G;Riccio A;Trono D
通讯作者：
Trono D
影响因子：
3.5
作者：
Nativio R;Sparago A;Ito Y;Weksberg R;Riccio A;Murrell A
通讯作者：
Murrell A