KCNQ1基因第二个内含子内的遗传变异影响CTCF结合，并在母系遗传时赋予患贝克威思-维德曼综合征的风险。

Genetic variants within the second intron of the KCNQ1 gene affect CTCF binding and confer a risk of Beckwith-Wiedemann syndrome upon maternal transmission.

作者信息

Demars Julie, Shmela Mansur Ennuri, Khan Abdul Waheed, Lee Kai Syin, Azzi Salah, Dehais Patrice, Netchine Irène, Rossignol Sylvie, Le Bouc Yves, El-Osta Assam, Gicquel Christine

机构信息

Epigenetics in Human Health and Disease, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia INRA, GenPhySE (Génétique, Physiologie et Systèmes d'Elevage), Castanet-Tolosan, France.

Epigenetics in Human Health and Disease, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Victoria, Australia.

出版信息

J Med Genet. 2014 Aug;51(8):502-11. doi: 10.1136/jmedgenet-2014-102368. Epub 2014 Jul 4.

DOI:10.1136/jmedgenet-2014-102368

PMID:24996904

Abstract

BACKGROUND

Disruption of 11p15 imprinting results in two fetal growth disorders with opposite phenotypes: the Beckwith-Wiedemann (BWS; MIM 130650) and the Silver-Russell (SRS; MIM 180860) syndromes. DNA methylation defects account for 60% of BWS and SRS cases and, in most cases, occur without any identified mutation in a cis-acting regulatory sequence or a trans-acting factor.

METHODS

We investigated whether 11p15 cis-acting sequence variants account for primary DNA methylation defects in patients with SRS and BWS with loss of DNA methylation at ICR1 and ICR2, respectively.

RESULTS

We identified a 4.5 kb haplotype that, upon maternal transmission, is associated with a risk of ICR2 loss of DNA methylation in patients with BWS. This novel region is located within the second intron of the KCNQ1 gene, 170 kb upstream of the ICR2 imprinting centre and encompasses two CTCF binding sites. We showed that, within the 4.5 kb region, two SNPs (rs11823023 and rs179436) affect CTCF occupancy at DNA motifs flanking the CTCF 20 bp core motif.

CONCLUSIONS

This study shows that genetic variants confer a risk of DNA methylation defect with a parent-of-origin effect and highlights the crucial role of CTCF for the regulation of genomic imprinting of the CDKN1C/KCNQ1 domain.

摘要

背景

11p15印记紊乱会导致两种具有相反表型的胎儿生长障碍：贝克威思-维德曼综合征（BWS；MIM 130650）和西尔弗-拉塞尔综合征（SRS；MIM 180860）。DNA甲基化缺陷占BWS和SRS病例的60%，并且在大多数情况下，发生时顺式作用调控序列或反式作用因子中没有任何已鉴定的突变。

方法

我们调查了11p15顺式作用序列变异是否导致SRS和BWS患者分别在ICR1和ICR2处出现DNA甲基化缺失的原发性DNA甲基化缺陷。

结果

我们鉴定出一个4.5 kb的单倍型，母系遗传时，它与BWS患者ICR2处DNA甲基化缺失的风险相关。这个新区域位于KCNQ1基因的第二个内含子内，在ICR2印记中心上游170 kb处，包含两个CTCF结合位点。我们发现，在4.5 kb区域内，两个单核苷酸多态性（rs11823023和rs179436）影响CTCF在CTCF 20 bp核心基序侧翼DNA基序上的占据情况。