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: Sánchez Delgado, Marta, Martín Trujillo, Alex, Tayama, Chiharu, Vidal, Enrique, Esteller, Manel, 1968-, Iglesias Platas, Isabel, Deo, Nandita, Barney, Olivia, Maclean, Ken, Hata, Kenichiro, Nakabayashi, Kazuhiko, Fisher, Rosemary, Monk, David
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2015
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/108383
Acceso en línea:https://hdl.handle.net/2445/108383
Access Level:acceso abierto
Palabra clave:Metilació
ADN
Mola hidatídica
Placenta
Genòmica
Mutació (Biologia)
Embaràs
Methylation
DNA
Hydatidiform mole
Genomics
Mutation (Biology)
Pregnancy
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spelling Absence of Maternal Methylation in Biparental Hydatidiform Moles from Women with NLRP7 Maternal-Effect Mutations Reveals Widespread Placenta-Specific ImprintingSánchez Delgado, MartaMartín Trujillo, AlexTayama, ChiharuVidal, EnriqueEsteller, Manel, 1968-Iglesias Platas, IsabelDeo, NanditaBarney, OliviaMaclean, KenHata, KenichiroNakabayashi, KazuhikoFisher, RosemaryMonk, DavidMetilacióADNMola hidatídicaPlacentaGenòmicaMutació (Biologia)EmbaràsMethylationDNAHydatidiform molePlacentaGenomicsMutation (Biology)PregnancyFamilial 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 placentaspecific 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 (PLoS)2015info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/108383Articles publicats en revistes (Ciències Fisiològiques)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1371/journal.pgen.1005644PLoS Genetics, 2015, vol. 11, num. 11, p. 1-17https://doi.org/10.1371/journal.pgen.1005644cc-by (c) Sanchez-Delgado, Marta et al., 2015http://creativecommons.org/licenses/by/3.0/esinfo:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1083832026-05-27T06:46:51Z
dc.title.none.fl_str_mv 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
spellingShingle Absence of Maternal Methylation in Biparental Hydatidiform Moles from Women with NLRP7 Maternal-Effect Mutations Reveals Widespread Placenta-Specific Imprinting
Sánchez Delgado, Marta
Metilació
ADN
Mola hidatídica
Placenta
Genòmica
Mutació (Biologia)
Embaràs
Methylation
DNA
Hydatidiform mole
Placenta
Genomics
Mutation (Biology)
Pregnancy
title_short 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_sort Absence of Maternal Methylation in Biparental Hydatidiform Moles from Women with NLRP7 Maternal-Effect Mutations Reveals Widespread Placenta-Specific Imprinting
dc.creator.none.fl_str_mv Sánchez Delgado, Marta
Martín Trujillo, Alex
Tayama, Chiharu
Vidal, Enrique
Esteller, Manel, 1968-
Iglesias Platas, Isabel
Deo, Nandita
Barney, Olivia
Maclean, Ken
Hata, Kenichiro
Nakabayashi, Kazuhiko
Fisher, Rosemary
Monk, David
author Sánchez Delgado, Marta
author_facet Sánchez Delgado, Marta
Martín Trujillo, Alex
Tayama, Chiharu
Vidal, Enrique
Esteller, Manel, 1968-
Iglesias Platas, Isabel
Deo, Nandita
Barney, Olivia
Maclean, Ken
Hata, Kenichiro
Nakabayashi, Kazuhiko
Fisher, Rosemary
Monk, David
author_role author
author2 Martín Trujillo, Alex
Tayama, Chiharu
Vidal, Enrique
Esteller, Manel, 1968-
Iglesias Platas, Isabel
Deo, Nandita
Barney, Olivia
Maclean, Ken
Hata, Kenichiro
Nakabayashi, Kazuhiko
Fisher, Rosemary
Monk, David
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Metilació
ADN
Mola hidatídica
Placenta
Genòmica
Mutació (Biologia)
Embaràs
Methylation
DNA
Hydatidiform mole
Placenta
Genomics
Mutation (Biology)
Pregnancy
topic Metilació
ADN
Mola hidatídica
Placenta
Genòmica
Mutació (Biologia)
Embaràs
Methylation
DNA
Hydatidiform mole
Placenta
Genomics
Mutation (Biology)
Pregnancy
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 placentaspecific 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.
publishDate 2015
dc.date.none.fl_str_mv 2015
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/108383
url https://hdl.handle.net/2445/108383
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1371/journal.pgen.1005644
PLoS Genetics, 2015, vol. 11, num. 11, p. 1-17
https://doi.org/10.1371/journal.pgen.1005644
dc.rights.none.fl_str_mv cc-by (c) Sanchez-Delgado, Marta et al., 2015
http://creativecommons.org/licenses/by/3.0/es
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Sanchez-Delgado, Marta et al., 2015
http://creativecommons.org/licenses/by/3.0/es
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Public Library of Science (PLoS)
publisher.none.fl_str_mv Public Library of Science (PLoS)
dc.source.none.fl_str_mv Articles publicats en revistes (Ciències Fisiològiques)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300719

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