{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T16:12:22Z","timestamp":1782231142874,"version":"3.54.5"},"reference-count":71,"publisher":"The Endocrine Society","issue":"2","license":[{"start":{"date-parts":[[2020,10,29]],"date-time":"2020-10-29T00:00:00Z","timestamp":1603929600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100006570","name":"Coordinaci\u00f3n de la Investigaci\u00f3n Cient\u00edfica","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006570","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003141","name":"Consejo Nacional de Ciencia y Tecnolog\u00eda","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003141","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,1,23]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Context<\/jats:title><jats:p>Follicle-stimulating hormone (FSH) plays an essential role in gonadal function. Loss-of-function mutations in the follicle-stimulating hormone receptor (FSHR) are an infrequent cause of primary ovarian failure.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>To analyze the molecular physiopathogenesis of a novel mutation in the FSHR identified in a woman with primary ovarian failure, employing in vitro and in silico approaches, and to compare the features of this dysfunctional receptor with those shown by the trafficking-defective D408Y FSHR mutant.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Sanger sequencing of the FSHR cDNA was applied to identify the novel mutation. FSH-stimulated cyclic adenosine monophosphate (cAMP) production, ERK1\/2 phosphorylation, and desensitization were tested in HEK293 cells. Receptor expression was analyzed by immunoblotting, receptor-binding assays, and flow cytometry. Molecular dynamics simulations were performed to determine the in silico behavior of the mutant FSHRs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A novel missense mutation (I423T) in the second transmembrane domain of the FSHR was identified in a woman with normal pubertal development but primary amenorrhea. The I423T mutation slightly impaired plasma membrane expression of the mature form of the receptor and severely impacted on cAMP\/protein kinase A signaling but much less on \u03b2-arrestin-dependent ERK1\/2 phosphorylation. Meanwhile, the D408Y mutation severely affected membrane expression, with most of the FSH receptor located intracellularly, and both signal readouts tested. Molecular dynamics simulations revealed important functional disruptions in both mutant FSHRs, mainly the loss of interhelical connectivity in the D408Y FSHR.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Concurrently, these data indicate that conformational differences during the inactive and active states account for the distinct expression levels, differential signaling, and phenotypic expression of the I423T and D408Y mutant FSHRs.<\/jats:p><\/jats:sec>","DOI":"10.1210\/clinem\/dgaa782","type":"journal-article","created":{"date-parts":[[2020,10,29]],"date-time":"2020-10-29T14:00:51Z","timestamp":1603980051000},"page":"e534-e550","source":"Crossref","is-referenced-by-count":22,"title":["A Novel Mutation in the FSH Receptor (I423T) Affecting Receptor Activation and Leading to Primary Ovarian Failure"],"prefix":"10.1210","volume":"106","author":[{"given":"Teresa","family":"Zari\u00f1\u00e1n","sequence":"first","affiliation":[{"name":"Red de Apoyo a la Investigaci\u00f3n, National University of Mexico-Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n, Mexico City, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julio","family":"Mayorga","sequence":"additional","affiliation":[{"name":"Department of Reproductive Biology, Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n, Mexico City, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3701-429X","authenticated-orcid":false,"given":"Eduardo","family":"Jard\u00f3n-Valadez","sequence":"additional","affiliation":[{"name":"Departamento de Recursos de la Tierra, Universidad Aut\u00f3noma Metropolitana, Unidad Lerma, Lerma, Edo. de Mexico, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rub\u00e9n","family":"Guti\u00e9rrez-Sagal","sequence":"additional","affiliation":[{"name":"Red de Apoyo a la Investigaci\u00f3n, National University of Mexico-Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n, Mexico City, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3755-662X","authenticated-orcid":false,"given":"Jos\u00e9 Luis","family":"Maravillas-Montero","sequence":"additional","affiliation":[{"name":"Red de Apoyo a la Investigaci\u00f3n, National University of Mexico-Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n, Mexico City, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy R","family":"Mej\u00eda-Dom\u00ednguez","sequence":"additional","affiliation":[{"name":"Red de Apoyo a la Investigaci\u00f3n, National University of Mexico-Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n, Mexico City, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iv\u00e1n","family":"Mart\u00ednez-Luis","sequence":"additional","affiliation":[{"name":"Red de Apoyo a la Investigaci\u00f3n, National University of Mexico-Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n, Mexico City, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omar G","family":"Yacini-Torres","sequence":"additional","affiliation":[{"name":"Red de Apoyo a la Investigaci\u00f3n, National University of Mexico-Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n, Mexico City, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ma-del-Carmen","family":"Cravioto","sequence":"additional","affiliation":[{"name":"Department of Reproductive Biology, Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n, Mexico City, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Reiter","sequence":"additional","affiliation":[{"name":"Physiologie de la Reproduction et des Comportements (PRC), Institut National de Recherche pour l\u2019Agriculture, l\u2019Alimentation et l\u2019Environnement (INRAE), Centre National de la Recherche Scientifique (CNRS), Universit\u00e9 de Tours, Tours, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9532-3886","authenticated-orcid":false,"given":"Alfredo","family":"Ulloa-Aguirre","sequence":"additional","affiliation":[{"name":"Red de Apoyo a la Investigaci\u00f3n, National University of Mexico-Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n, Mexico City, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2020,10,29]]},"reference":[{"issue":"6","key":"2021122205231756200_CIT0001","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.1124\/mol.63.6.1256","article-title":"The G-protein-coupled receptors in the human genome form five main families. 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