Faculty of Medicine, University of Southampton, Southampton, UK.
Eur J Hum Genet. 2012 Feb;20(2):240-3. doi: 10.1038/ejhg.2011.166. Epub 2011 Aug 24.
The imprinted expression of the IGF2 and H19 genes is controlled by the imprinting control region 1 (ICR1) located at chromosome 11p15.5. DNA methylation defects involving ICR1 result in two growth disorders with opposite phenotypes: an overgrowth disorder, the Beckwith-Wiedemann syndrome (maternal ICR1 hypermethylation in 10% of BWS cases) and a growth retardation disorder, the Silver-Russell syndrome (paternal ICR1 loss of methylation in 60% of SRS cases). In familial BWS, hypermethylation of ICR1 has been found in association with microdeletion of repetitive DNA motifs within ICR1 that bind the zinc finger protein CTCF; but more recently, ICR1 point mutations were described in BWS pedigrees. We present a case report of two brothers with BWS and prolonged post-pubertal growth resulting in very large stature. A maternally inherited point mutation was identified in ICR1 in both brothers, which altered binding of OCT transcription factors. The same mutation was present on the paternally inherited allele of their unaffected mother. This is a second report of a point mutation causing ICR1 hypermethylation by altering an OCT-binding motif. The atypical growth phenotype of the brothers may be connected to the unusual underlying cause of their BWS.
IGF2 和 H19 基因的印迹表达受位于 11p15.5 染色体上的印迹控制区 1 (ICR1) 控制。涉及 ICR1 的 DNA 甲基化缺陷导致两种表型相反的生长障碍：过度生长障碍，即 Beckwith-Wiedemann 综合征（10%的 BWS 病例中存在 ICR1 母体过度甲基化）和生长迟缓障碍，即 Silver-Russell 综合征（60%的 SRS 病例中存在 ICR1 父系甲基化缺失）。在家族性 BWS 中，ICR1 的异常甲基化与 ICR1 内结合锌指蛋白 CTCF 的重复 DNA 基序的微缺失有关；但最近，在 BWS 家系中描述了 ICR1 点突变。我们报告了两例 BWS 兄弟的病例，他们在青春期后持续生长，导致身材非常高大。在两兄弟的 ICR1 中均发现了一个母系遗传的点突变，该突变改变了 OCT 转录因子的结合。他们未受影响的母亲的父系遗传等位基因上也存在相同的突变。这是第二个报道的通过改变 OCT 结合基序导致 ICR1 异常甲基化的点突变。兄弟俩的非典型生长表型可能与其 BWS 的异常潜在原因有关。
