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Absence of Maternal Methylation in Biparental Hydatidiform Moles from Women with NLRP7 Maternal-Effect Mutations Reveals Widespread Placenta-Specific Imprinting

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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4636177/
https://www.ncbi.nlm.nih.gov/pubmed/26544189
http://dx.doi.org/10.1371/journal.pgen.1005644
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author 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
author_facet 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
author_sort Sanchez-Delgado, Marta
collection PubMed
description 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.
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spelling pubmed-46361772015-11-13 Absence of Maternal Methylation in Biparental Hydatidiform Moles from Women with NLRP7 Maternal-Effect Mutations Reveals Widespread Placenta-Specific Imprinting 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 PLoS Genet Research Article 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. Public Library of Science 2015-11-06 /pmc/articles/PMC4636177/ /pubmed/26544189 http://dx.doi.org/10.1371/journal.pgen.1005644 Text en © 2015 Sanchez-Delgado et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
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
Absence of Maternal Methylation in Biparental Hydatidiform Moles from Women with NLRP7 Maternal-Effect Mutations Reveals Widespread Placenta-Specific Imprinting
title Absence of Maternal Methylation in Biparental Hydatidiform Moles from Women with NLRP7 Maternal-Effect Mutations Reveals Widespread Placenta-Specific Imprinting
title_full Absence of Maternal Methylation in Biparental Hydatidiform Moles from Women with NLRP7 Maternal-Effect Mutations Reveals Widespread Placenta-Specific Imprinting
title_fullStr Absence of Maternal Methylation in Biparental Hydatidiform Moles from Women with NLRP7 Maternal-Effect Mutations Reveals Widespread Placenta-Specific Imprinting
title_full_unstemmed Absence of Maternal Methylation in Biparental Hydatidiform Moles from Women with NLRP7 Maternal-Effect Mutations Reveals Widespread Placenta-Specific Imprinting
title_short Absence of Maternal Methylation in Biparental Hydatidiform Moles from Women with NLRP7 Maternal-Effect Mutations Reveals Widespread Placenta-Specific Imprinting
title_sort absence of maternal methylation in biparental hydatidiform moles from women with nlrp7 maternal-effect mutations reveals widespread placenta-specific imprinting
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4636177/
https://www.ncbi.nlm.nih.gov/pubmed/26544189
http://dx.doi.org/10.1371/journal.pgen.1005644
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