Silver-Russell patients showing a broad range of ICR1 and ICR2 hypomethylation in different tissues
Silver-Russell patients showing a broad range of ICR1 and ICR2 hypomethylation in different tissues
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DOI：
10.1111/j.1399-0004.2010.01514.x
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发表时间：
2011-07-01
影响因子：
3.5
通讯作者：
Eggermann, T.
中科院分区：
文献类型：
--
作者：
Begemann, M.;Spengler, S.;Eggermann, T.
在所有已知的先天性印迹疾病中，与特定基因座的异常甲基化或突变的关联已经得到了很好的建立。然而，同时描述了几例表现出多位点低甲基化（MLH）的短暂性新生儿糖尿病（TNDM）、Silver-Russell综合征（SRS）和Beckwith-Wiedemann综合征（BWS）患者。而TNDM患者的MLH表现出不同的临床症状与孤立的6 q24畸变的携带者，MLH携带者诊断为BWS或SRS只呈现症状特异性的功能。有趣的是，SRS和BWS患者的白细胞MLH模式几乎相同。我们现在报告的分子研究结果在DNA中的三个SRS患者与低甲基化的11 p15印迹控制区（ICR）的白细胞。一名患者是单卵（MZ）双胞胎，另一个是三胞胎。虽然低甲基化影响白细胞中的两个相反印记的11 p15 ICR，但在我们的两名患者中，在口腔拭子DNA中仅ICR 1低甲基化可见。在这些患者之一的未受影响的MZ双胞胎中，白细胞中也存在异常甲基化，但颊拭子DNA和皮肤成纤维细胞中均不存在异常甲基化。尽管对参与甲基化标记的建立和维持的几个因子进行了突变筛查，包括ZFP 57、MBD 3、DNMT 1和DNMT 3L，但我们患者中ICR 1/ICR 2低甲基化的分子线索仍不清楚。此外，特定SRS表型发展的原因并不明显。总之，我们的数据反映了广泛的表位突变的SRS和说明，广泛的分子和临床表征的患者是必要的。
In all known congenital imprinting disorders an association with aberrant methylation or mutations at specific loci was well established. However, several patients with transient neonatal diabetes mellitus (TNDM), Silver-Russell syndrome (SRS) and Beckwith-Wiedemann syndrome (BWS) exhibiting multilocus hypomethylation (MLH) have meanwhile been described. Whereas TNDM patients with MLH show clinical symptoms different from carriers with isolated 6q24 aberrations, MLH carriers diagnosed as BWS or SRS present only the syndrome-specific features. Interestingly, SRS and BWS patients with nearly identical MLH patterns in leukocytes have been identified. We now report on the molecular findings in DNA in three SRS patients with hypomethylation of both 11p15 imprinted control regions (ICRs) in leukocytes. One patient was a monozygotic (MZ) twin, another was a triplet. While the hypomethylation affected both oppositely imprinted 11p15 ICRs in leukocytes, in buccal swab DNA only the ICR1 hypomethylation was visible in two of our patients. In the non-affected MZ twin of one of these patients, aberrant methylation was also present in leukocytes but neither in buccal swab DNA nor in skin fibroblasts. Despite mutation screening of several factors involved in establishment and maintenance of methylation marks including ZFP57, MBD3, DNMT1 and DNMT3L the molecular clue for the ICR1/ICR2 hypomethylation in our patients remained unclear. Furthermore, the reason for the development of the specific SRS phenotype is not obvious. In conclusion, our data reflect the broad range of epimutations in SRS and illustrate that an extensive molecular and clinical characterization of patients is necessary.