Temple syndrome in a patient with variably methylated CpGs at the primary MEG3/DLK1:IG-DMR and severely hypomethylated CpGs at the secondary MEG3:TSS-DMR
Temple syndrome in a patient with variably methylated CpGs at the primary MEG3/DLK1:IG-DMR and severely hypomethylated CpGs at the secondary MEG3:TSS-DMR
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DOI：
10.1186/s13148-019-0640-2
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发表时间：
2019-03-07
影响因子：
5.7
通讯作者：
Ogata, Tsutomu
中科院分区：
文献类型：
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作者：
Kagami, Masayo;Yanagisawa, Atsuhiro;Ogata, Tsutomu
背景人类染色体 14q32.2 印记区域包含初级 MEG3/DLK1:IG 差异甲基化区域 (DMR) 和次级 MEG3:TSS-DMR。 MEG3:TSS-DMR 仅在体组织中存在未甲基化的 MEG3/DLK1:IG-DMR 时才能保持非甲基化，但在胎盘中则不然，因为两个 DMR 之间的甲基化模式存在分级调节。方法我们对一名患有 Temple 综合征 (TS14) 的 4 岁日本女孩进行了分子研究。结果焦磷酸测序分析显示，在白细胞中 MEG3:TSS-DMR 和 MEG3/DLK1:IG-DMR 处四个 CpG 的甲基化水平大致正常。 HumanMmethylation450 BeadChip 证实了白细胞中 MEG3:TSS-DMR 的显着低甲基化，并揭示了多位点印迹干扰 (MLID)，包括 H19/IGF2:IG-DMR 的轻度低甲基化和 GNAS A/B:TSS-DMR 的轻度高甲基化。亚硫酸氢盐测序显示白细胞中 MEG3:TSS-DMR 处的 CpG 明显低甲基化，MEG3/DLK1:IG-DMR 处的 CpG 不规则且无差异甲基化，胎盘中两个 DMR 的甲基化模式明显正常。排除了母体单亲二倍体 14 和涉及该印记区域的缺失。结论 在 TS14 患者中尚未报道 MEG3/DLK1:IG-DMR 的这种甲基化模式。 MEG3/DLK1:IG-DMR 上一定程度的不规则低甲基化可能阻止了体组织中 MEG3:TSS-DMR 的甲基化，并且 MEG3/DLK1:IG-DMR 上发生了高甲基化型 MLID，从而在胎盘中产生了明显正常的甲基化模式。
BackgroundThe human chromosome 14q32.2 imprinted region harbors the primary MEG3/DLK1:IG-differentially methylated region (DMR) and secondary MEG3:TSS-DMR. The MEG3:TSS-DMR can remain unmethylated only in the presence of unmethylated MEG3/DLK1:IG-DMR in somatic tissues, but not in the placenta, because of a hierarchical regulation of the methylation pattern between the two DMRs.MethodsWe performed molecular studies in a 4-year-old Japanese girl with Temple syndrome (TS14).ResultsPyrosequencing analysis showed extremely low methylation levels of five CpGs at the MEG3:TSS-DMR and grossly normal methylation levels of four CpGs at the MEG3/DLK1:IG-DMR in leukocytes. HumanMethylation450 BeadChip confirmed marked hypomethylation of the MEG3:TSS-DMR and revealed multilocus imprinting disturbance (MLID) including mild hypomethylation of the H19/IGF2:IG-DMR and mild hypermethylation of the GNAS A/B:TSS-DMR in leukocytes. Bisulfite sequencing showed markedly hypomethylated CpGs at the MEG3:TSS-DMR and irregularly and non-differentially methylated CpGs at the MEG3/DLK1:IG-DMR in leukocytes and apparently normal methylation patterns of the two DMRs in the placenta. Maternal uniparental disomy 14 and a deletion involving this imprinted region were excluded.ConclusionsSuch a methylation pattern of the MEG3/DLK1:IG-DMR has not been reported in patients with TS14. It may be possible that a certain degree of irregular hypomethylation at the MEG3/DLK1:IG-DMR has prevented methylation of the MEG3:TSS-DMR in somatic tissues and that a hypermethylation type MLID has occurred at the MEG3/DLK1:IG-DMR to yield the apparently normal methylation pattern in the placenta.