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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

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

PROVIDER: PRJNA641739 | ENA |

REPOSITORIES: ENA

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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.

2020-10-02 | GSE153211 | GEO

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

Project description:BackgroundPADI6 is a component of the subcortical maternal complex, a group of proteins that is abundantly expressed in the oocyte cytoplasm, but is required for the correct development of early embryo. Maternal-effect variants of the subcortical maternal complex proteins are associated with heterogeneous diseases, including female infertility, hydatidiform mole, and imprinting disorders with multi-locus imprinting disturbance. While the involvement of PADI6 in infertility is well demonstrated, its role in imprinting disorders is less well established.ResultsWe have identified by whole-exome sequencing analysis four cases of Beckwith-Wiedemann syndrome with multi-locus imprinting disturbance whose mothers are carriers of PADI6 variants. In silico analysis indicates that these variants result in loss of function, and segregation analysis suggests they act as either recessive or dominant-negative maternal-effect mutations. Genome-wide methylation analysis revealed heterogeneous and extensively altered methylation profiles of imprinted loci in the patients, including two affected sisters, but not in their healthy siblings.ConclusionOur results firmly establish the role of PADI6 in imprinting disorders. We report loss-of-function maternal-effect variants of PADI6 that are associated with heterogeneous multi-locus imprinting disturbances in the progeny. The rare finding of two siblings affected by Beckwith-Wiedemann syndrome suggests that in some cases, familial recurrence risk of these variants may be high. However, the heterogeneous phenotypes of the other pedigrees suggest that altered oocyte PADI6 function results in stochastic maintenance of methylation imprinting with unpredictable consequences on early embryo health.

| S-EPMC7489023 | biostudies-literature

Multi-omic Investigation of Beckwith-Wiedemann Syndrome Hepatoblasto

Project description:Multi-omic Investigation of Beckwith-Wiedemann Syndrome Hepatoblasto

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Multi-omic Investigation of Beckwith-Wiedemann Syndrome Hepatoblasto

Project description:Multi-omic Investigation of Beckwith-Wiedemann Syndrome Hepatoblasto

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Multi-omic Investigation of Beckwith-Wiedemann Syndrome Wilms Tumor

Project description:Multi-omic Investigation of Beckwith-Wiedemann Syndrome Wilms Tumor

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Project description:Multi-omic Investigation of Beckwith-Wiedemann Syndrome Wilms Tumor

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Co-occurrence of Beckwith–Wiedemann Syndrome and colorectal cancer in a young woman

Project description:Beckwith-Wiedemann Spectrum (BWSp) is a disorder predisposing to tumors of embryonic origin that arise during childhood. Little is known concerning the tumor risk and histotype prevalence in adult BWSp patients. However, several studies report cases of co-occurrence of BWSp and tumors in early adulthood, suggesting that the cancer risk in BWSp could be relevant also later than childhood. Here, we report for the first time a case of co-occurrence of BWSp and early-onset colorectal cancer (EO-CRC). The results disclosed genetic and epigenetic molecular lesions of the patient at both somatic and germline levels, providing support to the hypothesis that epigenetic changes contribute to cancer initiation in tissues where a genetic insult is already present, acting in a cooperative manner to stimulate tumorigenesis.

2023-04-01 | GSE224222 | GEO

A maternal-effect Padi6 variant causes nuclear and cytoplasmic abnormalities in oocytes as well as failure of epigenetic reprogramming and zygotic genome activation in embryos [WGS]

Project description:Maternal inactivation of genes encoding components of the sub-cortical maternal complex (SCMC) and its associated member PADI6 generally results in early embryo lethality. In humans, SCMC gene variants were found in the healthy mothers of children affected by multi-locus imprinting disturbances (MLID). However, how the SCMC controls the DNA methylation required to regulate imprinting remains poorly defined. We generated a mouse line carrying a Padi6 missense variant that was identified in a family with Beckwith-Wiedemann syndrome and MLID. If homozygous in female mice this variant resulted in interruption of embryo development at the 2-cell stage. Single-cell multi-omic analyses demonstrated defective maturation of Padi6-mutant oocytes and incomplete DNA demethylation, down-regulation of zygotic genome activation (ZGA) genes, up-regulation of maternal decay genes and developmental delay in 2-cell embryos developing from Padi6-mutant oocytes, but little effect on genomic imprinting. Western blotting and immunofluorescence analyses showed reduced level of UHRF1 in oocytes and abnormal localization of DNMT1 and UHRF1 in both oocytes and zygotes. Treatment with 5-azacytidine reverted DNA hypermethylation but did not rescue the developmental arrest of mutant embryos. Taken together, this study demonstrates that PADI6 controls both nuclear and cytoplasmic oocyte processes that are necessary for pre-implantation epigenetic reprogramming and ZGA.

2023-10-18 | GSE245425 | GEO