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Impaired DNA methylation in oocytes with a mutation in KHDC3L causing recurrent hydatidiform mole

ABSTRACT: Mutations in components of the subcortical maternal complex (SMC) of the human oocyte are enigmatically associated with DNA methylation abnormalities specifically at imprinted genes in conceptuses, but the developmental timing, genomic extent and mechanistic details of these defects are unknown. Here, we show, by single-cell bisulphite sequencing, that mutation in human KHDC3L that causes recurrent hydatidiform mole results in a genome-wide deficit of de novo methylation in oocytes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE122872 | GEO | 2019/11/21

REPOSITORIES: GEO

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A KHDC3L mutation resulting in recurrent hydatidiform mole causes genome-wide DNA methylation loss in oocytes and persistent imprinting defects post-fertilisation.

Project description:Maternal-effect mutations in components of the subcortical maternal complex (SCMC) of the human oocyte can cause early embryonic failure, gestational abnormalities and recurrent pregnancy loss. Enigmatically, they are also associated with DNA methylation abnormalities at imprinted genes in conceptuses, in the devastating gestational abnormality biparental complete hydatidiform mole (BiCHM) or in multi-locus imprinting disease (MLID). However, the developmental timing, genomic extent and mechanistic basis of these imprinting defects are unknown. Here, we studied methylation level of a women reported with familial recurrent hydatidiform mole and multiple pregnancy loss. Genotype analysis revealed homozygous mutation in KHDC3L. We obtained biparental mole from patient (Patient D) and compared it’s whole-genome methylation profile with respect to control placentas and sporadic mole (AnCHM) using Infinium MethylationEPIC BeadChip (WG-317-1001, Illumina). We also used endometrium samples from their respective mother for the comparison purposes. Molar conceptuses were observed with methylation defects at genome-wide level and profound loss of methylation at multiple genome-derived differentially methylated regions (gDMRs) confirming MLID.

2019-11-21 | GSE138864 | GEO

Impaired DNA methylation in oocytes with a mutation in KHDC3L causing recurrent hydatidiform mole

Project description:Impaired DNA methylation in oocytes with a mutation in KHDC3L causing recurrent hydatidiform mole

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Loss-of-function maternal-effect mutations of PADI6 are associated with familial and sporadic Beckwith-Wiedemann Syndrome with multi-locus imprinting disturbance

Project description:PADI6 is a component of the subcortical maternal complex (SCMC) which is a group of proteins that are abundantly expressed in the oocyte cytoplasm and essential for the proper development of the early embryo. The mutation(s) in the components of the subcortical maternal complex have been associated with reproductive failures, including formation of hydatidiform mole, female infertility and imprinting disorders with multi-locus imprinting disturbance (MLIDs).In the current study by using whole-exome sequencing analysis, we identified four cases of Beckwith-Wiedemann Syndrome with multi-locus imprinting disturbance while their mothers were carriers of variants in PADI6 gene. Genome-wide methylation profiling using Methylation EPIC array depicted the loss of methylation specifically at several known imprinted loci in affected individuals as compared to healthy siblings, parents and controls. Our findings firmly establish the role of PADI6 in imprinting disorders.

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Methylation profiling of hydatidiform moles

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A Patient specific iPSC-based model of Hydatidiform mole reveals abnormal BMP4 signaling caused by NLRP7 deficiency

Project description:Complete Hydatidiform Mole (HM) is a gestational trophoblastic disease resulting in hyper proliferation of trophoblast cells and absence of embryo development. Mutations in NLRP7 gene is a major cause of familial recurrent complete HM, where no embryonic tissue is present during the pregnancy. NLRP7 is a novel protein and its function is poorly understood. Lack of NLRP7 in the mouse genome and challenges in studying human embryogenesis as well as human trophoblast differentiation has prevented elucidation of the pathophysiology of this disease and the function of NLRP7 in HM. Here, we established an in vitro model of HM using NLRP7 deficient patient-derived human induced pluripotent stem cells (iPSCs). Whole transcriptome profiling during trophoblast differentiation revealed that NLRP7 deficiency results in precocious downregulation of pluripotency factors, activation of trophoblast genes and promotes maturation of differentiated extraembryonic cell types such as syncytiotrophoblasts. We further showed that these phenotypes are dependent on BMP4 signaling and BMP pathway inhibition prevented excessive trophoblast differentiation of HM-iPSCs. Taken together, this novel human iPSC model of a genetic placental disease recapitulates aspect of trophoblast biology and sheds light on early human embryogenesis by identifying NLRP7 as an important regulator of this process.

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A Novel Approach Identifies New Differentially Methylated Regions (DMRs) Associated with Imprinted Genes

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Methylation studies in mole rats. Part 2

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A Patient specific iPSC-based model of Hydatidiform mole reveals abnormal BMP4 signaling caused by NLRP7 deficiency

Project description:A Patient specific iPSC-based model of Hydatidiform mole reveals abnormal BMP4 signaling caused by NLRP7 deficiency

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2010-05-17 | E-GEOD-18701 | biostudies-arrayexpress

A KHDC3L mutation resulting in recurrent hydatidiform mole causes genome-wide DNA methylation loss in oocytes and persistent imprinting defects post-fertilisation.

Project description:A KHDC3L mutation resulting in recurrent hydatidiform mole causes genome-wide DNA methylation loss in oocytes and persistent imprinting defects post-fertilisation.

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