Sanchez-Delgado Marta, Martin-Trujillo Alejandro, Tayama Chiharu, Vidal Enrique, Esteller Manel, Iglesias-Platas Isabel, Deo Nandita, Barney Olivia, Maclean Ken, Hata Kenichiro, Nakabayashi Kazuhiko, Fisher Rosemary, Monk David
Imprinting and Cancer Group, Cancer Epigenetic and Biology Program, Institut d'Investigació Biomedica de Bellvitge, Hospital Duran i Reynals, Barcelona, Spain.
Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan.
PLoS Genet. 2015 Nov 6;11(11):e1005644. doi: 10.1371/journal.pgen.1005644. eCollection 2015 Nov.
Familial recurrent hydatidiform mole (RHM) is a maternal-effect autosomal recessive disorder usually associated with mutations of the NLRP7 gene. It is characterized by HM with excessive trophoblastic proliferation, which mimics the appearance of androgenetic molar conceptuses despite their diploid biparental constitution. It has been proposed that the phenotypes of both types of mole are associated with aberrant genomic imprinting. However no systematic analyses for imprinting defects have been reported. Here, we present the genome-wide methylation profiles of both spontaneous androgenetic and biparental NLRP7 defective molar tissues. We observe total paternalization of all ubiquitous and placenta-specific differentially methylated regions (DMRs) in four androgenetic moles; namely gain of methylation at paternally methylated loci and absence of methylation at maternally methylated regions. The methylation defects observed in five RHM biopsies from NLRP7 defective patients are restricted to lack-of-methylation at maternal DMRs. Surprisingly RHMs from two sisters with the same missense mutations, as well as consecutive RHMs from one affected female show subtle allelic methylation differences, suggesting inter-RHM variation. These epigenotypes are consistent with NLRP7 being a maternal-effect gene and involved in imprint acquisition in the oocyte. In addition, bioinformatic screening of the resulting methylation datasets identified over sixty loci with methylation profiles consistent with imprinting in the placenta, of which we confirm 22 as novel maternally methylated loci. These observations strongly suggest that the molar phenotypes are due to defective placenta-specific imprinting and over-expression of paternally expressed transcripts, highlighting that maternal-effect mutations of NLRP7 are associated with the most severe form of multi-locus imprinting defects in humans.
家族性复发性葡萄胎（RHM）是一种母系效应常染色体隐性疾病，通常与NLRP7基因突变有关。其特征是葡萄胎伴有过度的滋养层细胞增殖，尽管其具有二倍体双亲组成，但外观类似孤雄来源的葡萄胎妊娠产物。有人提出，两种类型葡萄胎的表型都与异常的基因组印记有关。然而，尚未有关于印记缺陷的系统分析报道。在此，我们展示了自发孤雄来源和双亲来源的NLRP7缺陷型葡萄胎组织的全基因组甲基化谱。我们观察到，在四个孤雄来源的葡萄胎中，所有普遍存在的和胎盘特异性的差异甲基化区域（DMR）都完全呈现父系化状态；即在父系甲基化位点甲基化增加，而在母系甲基化区域无甲基化。在来自NLRP7缺陷患者的五份RHM活检样本中观察到的甲基化缺陷仅限于母系DMR处甲基化缺失。令人惊讶的是，来自具有相同错义突变的两姐妹的RHM，以及来自一名受影响女性的连续RHM显示出细微的等位基因甲基化差异，表明不同RHM之间存在变异。这些表观基因型与NLRP7作为母系效应基因并参与卵母细胞印记获得的情况一致。此外，对所得甲基化数据集的生物信息学筛选确定了六十多个位点，其甲基化谱与胎盘中的印记一致，其中我们确认22个为新的母系甲基化位点。这些观察结果强烈表明，葡萄胎表型是由于胎盘特异性印记缺陷和父系表达转录本的过度表达所致，突出了NLRP7的母系效应突变与人类中最严重形式的多位点印记缺陷相关。
