Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.
Limbach Humangenetik Berlin Kudamm, Berlin, Germany.
Eur J Hum Genet. 2019 Jun;27(6):903-908. doi: 10.1038/s41431-019-0365-x. Epub 2019 Feb 18.
Beckwith-Wiedemann syndrome (BWS; OMIM #130650) is an imprinting disorder caused by genetic or epigenetic alterations of one or both imprinting control regions on chromosome 11p15.5. Hypomethylation of the centromeric imprinting control region (KCNQ1OT1:TSS-DMR, ICR2) is the most common molecular cause of BWS and is present in about half of the cases. Based on a BWS family with a maternal deletion of the 5' part of KCNQ1 we have recently hypothesised that transcription of KCNQ1 is a prerequisite for the establishment of methylation at the KCNQ1OT1:TSS-DMR in the oocyte. Further evidence for this hypothesis came from a mouse model where methylation failed to be established when a poly(A) truncation cassette was inserted into this locus to prevent transcription through the DMR. Here we report on a family where a balanced translocation disrupts the KCNQ1 gene in intron 9. Maternal inheritance of this translocation is associated with hypomethylation of the KCNQ1OT1:TSS-DMR and BWS. This finding strongly supports our previous hypothesis that transcription of KCNQ1 is required for establishing the maternal methylation imprint at the KCNQ1OT1:TSS-DMR.
贝-威二氏综合征（BWS；OMIM #130650）是一种印记障碍，由 11p15.5 染色体上一个或两个印记控制区域的遗传或表观遗传改变引起。着丝粒印记控制区（KCNQ1OT1:TSS-DMR，ICR2）的低甲基化是 BWS 最常见的分子原因，约占一半病例。基于一个具有 KCNQ1 5'部分母系缺失的 BWS 家族，我们最近假设 KCNQ1 的转录是卵母细胞中 KCNQ1OT1:TSS-DMR 甲基化建立的前提。这一假设的进一步证据来自于一个小鼠模型，其中当在该基因座插入 poly(A)截断盒以阻止通过 DMR 的转录时，甲基化未能建立。在这里，我们报道了一个家族，其中平衡易位破坏了 KCNQ1 基因的 9 号内含子。这种易位的母系遗传与 KCNQ1OT1:TSS-DMR 的低甲基化和 BWS 有关。这一发现有力地支持了我们之前的假设，即 KCNQ1 的转录是建立 KCNQ1OT1:TSS-DMR 母系甲基化印记所必需的。
