BMPR1A and BMPR1B Missense Mutations Cause Primary Ovarian Insufficiency

CONTEXT: Primary ovarian insufficiency (POI) is a frequently occurring disorder affecting approximately 1% of women under 40 years of age. POI, which is characterized by the premature depletion of ovarian follicles and elevated plasma levels of follicle-stimulating hormone, leads to infertility. Alt...

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Autores:
Tipo de recurso:
Fecha de publicación:
2020
Institución:
Universidad del Rosario
Repositorio:
Repositorio EdocUR - U. Rosario
Idioma:
eng
OAI Identifier:
oai:repository.urosario.edu.co:10336/23371
Acceso en línea:
https://doi.org/10.1210/clinem/dgz226
https://repository.urosario.edu.co/handle/10336/23371
Palabra clave:
Bone morphogenic protein receptor
Follicular development
Infertility
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id EDOCUR2_ca73822c655780d8fa268aeb894c2748
oai_identifier_str oai:repository.urosario.edu.co:10336/23371
network_acronym_str EDOCUR2
network_name_str Repositorio EdocUR - U. Rosario
repository_id_str
spelling ebb21d05-6795-4b53-b3a8-3c1b76876f4f-177273e86-df40-4d8e-90a6-4e1c78ea40d6-15643f674-ea81-4f8c-9269-b42ae0baf9d7-14c21c987-eb06-4b96-ad35-8c9d99daef4a-17edfad1e-b100-49f3-8835-08c0ad0ab30e-179782770-10e716caf-e5ec-49bd-9955-66d1f21ea8f6-18d0624f6-6054-4c8f-a5ed-9d5a431503a2-12020-05-26T00:01:28Z2020-05-26T00:01:28Z2020CONTEXT: Primary ovarian insufficiency (POI) is a frequently occurring disorder affecting approximately 1% of women under 40 years of age. POI, which is characterized by the premature depletion of ovarian follicles and elevated plasma levels of follicle-stimulating hormone, leads to infertility. Although various etiological factors have been described, including chromosomal abnormalities and gene mutations, most cases remain idiopathic. OBJECTIVE: To identify and to functionally validate new sequence variants in 2 genes that play a key role in mammalian ovarian function, BMPR1A and BMPR1B (encoding for bone morphogenic protein receptor), leading to POI. METHODS: The impact on bone morphogenic protein (BMP) signaling of BMPR1A and BMPR1B variants, previously identified by whole-exome sequencing on 69 women affected by isolated POI, was established by different in vitro functional experiments. RESULTS: We demonstrate that the BMPR1A-p.Arg442His and BMPR1B-p.Phe272Leu variants are correctly expressed and located but lead to an impairment of downstream BMP signaling. CONCLUSION: In accordance with infertility observed in mice lacking Bmpr1a in the ovaries and in Bmpr1b-/- mice, our results unveil, for the first time, a link between BMPR1A and BMPR1B variants and the origin of POI. We show that BMP signaling impairment through specific BMPR1A and BMPR1B variants is a novel pathophysiological mechanism involved in human POI. We consider that BMPR1A and BMPR1B variants constitute genetic biomarkers of the origin of POI and have clinical utility. © Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.application/pdfhttps://doi.org/10.1210/clinem/dgz226https://repository.urosario.edu.co/handle/10336/23371engNLM (Medline)No. 4The Journal of clinical endocrinology and metabolismVol. 105The Journal of clinical endocrinology and metabolism, Vol.105, No.4 (2020)https://www.scopus.com/inward/record.uri?eid=2-s2.0-85081945965&doi=10.1210%2fclinem%2fdgz226&partnerID=40&md5=5db06b813c1defcea2896860b266c1adAbierto (Texto Completo)http://purl.org/coar/access_right/c_abf2instname:Universidad del Rosarioreponame:Repositorio Institucional EdocURBone morphogenic protein receptorFollicular developmentInfertilityBMPR1A and BMPR1B Missense Mutations Cause Primary Ovarian InsufficiencyarticleArtículohttp://purl.org/coar/version/c_970fb48d4fbd8a85http://purl.org/coar/resource_type/c_6501Renault, LuciePatiño, Liliana CMagnin, FrançoiseDelemer, BrigitteYoung, JacquesLaissue, PaulBinart, NadineBeau, Isabelle10336/23371oai:repository.urosario.edu.co:10336/233712022-05-02 07:37:20.939897https://repository.urosario.edu.coRepositorio institucional EdocURedocur@urosario.edu.co
dc.title.spa.fl_str_mv BMPR1A and BMPR1B Missense Mutations Cause Primary Ovarian Insufficiency
title BMPR1A and BMPR1B Missense Mutations Cause Primary Ovarian Insufficiency
spellingShingle BMPR1A and BMPR1B Missense Mutations Cause Primary Ovarian Insufficiency
Bone morphogenic protein receptor
Follicular development
Infertility
title_short BMPR1A and BMPR1B Missense Mutations Cause Primary Ovarian Insufficiency
title_full BMPR1A and BMPR1B Missense Mutations Cause Primary Ovarian Insufficiency
title_fullStr BMPR1A and BMPR1B Missense Mutations Cause Primary Ovarian Insufficiency
title_full_unstemmed BMPR1A and BMPR1B Missense Mutations Cause Primary Ovarian Insufficiency
title_sort BMPR1A and BMPR1B Missense Mutations Cause Primary Ovarian Insufficiency
dc.subject.keyword.spa.fl_str_mv Bone morphogenic protein receptor
Follicular development
Infertility
topic Bone morphogenic protein receptor
Follicular development
Infertility
description CONTEXT: Primary ovarian insufficiency (POI) is a frequently occurring disorder affecting approximately 1% of women under 40 years of age. POI, which is characterized by the premature depletion of ovarian follicles and elevated plasma levels of follicle-stimulating hormone, leads to infertility. Although various etiological factors have been described, including chromosomal abnormalities and gene mutations, most cases remain idiopathic. OBJECTIVE: To identify and to functionally validate new sequence variants in 2 genes that play a key role in mammalian ovarian function, BMPR1A and BMPR1B (encoding for bone morphogenic protein receptor), leading to POI. METHODS: The impact on bone morphogenic protein (BMP) signaling of BMPR1A and BMPR1B variants, previously identified by whole-exome sequencing on 69 women affected by isolated POI, was established by different in vitro functional experiments. RESULTS: We demonstrate that the BMPR1A-p.Arg442His and BMPR1B-p.Phe272Leu variants are correctly expressed and located but lead to an impairment of downstream BMP signaling. CONCLUSION: In accordance with infertility observed in mice lacking Bmpr1a in the ovaries and in Bmpr1b-/- mice, our results unveil, for the first time, a link between BMPR1A and BMPR1B variants and the origin of POI. We show that BMP signaling impairment through specific BMPR1A and BMPR1B variants is a novel pathophysiological mechanism involved in human POI. We consider that BMPR1A and BMPR1B variants constitute genetic biomarkers of the origin of POI and have clinical utility. © Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
publishDate 2020
dc.date.accessioned.none.fl_str_mv 2020-05-26T00:01:28Z
dc.date.available.none.fl_str_mv 2020-05-26T00:01:28Z
dc.date.created.spa.fl_str_mv 2020
dc.type.eng.fl_str_mv article
dc.type.coarversion.fl_str_mv http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.coar.fl_str_mv http://purl.org/coar/resource_type/c_6501
dc.type.spa.spa.fl_str_mv Artículo
dc.identifier.doi.none.fl_str_mv https://doi.org/10.1210/clinem/dgz226
dc.identifier.uri.none.fl_str_mv https://repository.urosario.edu.co/handle/10336/23371
url https://doi.org/10.1210/clinem/dgz226
https://repository.urosario.edu.co/handle/10336/23371
dc.language.iso.spa.fl_str_mv eng
language eng
dc.relation.citationIssue.none.fl_str_mv No. 4
dc.relation.citationTitle.none.fl_str_mv The Journal of clinical endocrinology and metabolism
dc.relation.citationVolume.none.fl_str_mv Vol. 105
dc.relation.ispartof.spa.fl_str_mv The Journal of clinical endocrinology and metabolism, Vol.105, No.4 (2020)
dc.relation.uri.spa.fl_str_mv https://www.scopus.com/inward/record.uri?eid=2-s2.0-85081945965&doi=10.1210%2fclinem%2fdgz226&partnerID=40&md5=5db06b813c1defcea2896860b266c1ad
dc.rights.coar.fl_str_mv http://purl.org/coar/access_right/c_abf2
dc.rights.acceso.spa.fl_str_mv Abierto (Texto Completo)
rights_invalid_str_mv Abierto (Texto Completo)
http://purl.org/coar/access_right/c_abf2
dc.format.mimetype.none.fl_str_mv application/pdf
dc.publisher.spa.fl_str_mv NLM (Medline)
institution Universidad del Rosario
dc.source.instname.spa.fl_str_mv instname:Universidad del Rosario
dc.source.reponame.spa.fl_str_mv reponame:Repositorio Institucional EdocUR
repository.name.fl_str_mv Repositorio institucional EdocUR
repository.mail.fl_str_mv edocur@urosario.edu.co
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