R31C GNRH1 mutation and congenital hypogonadotropic hypogonadism.

Normosmic congenital hypogonadotropic hypogonadism (nCHH) is a rare reproductive disease leading to lack of puberty and infertility. Loss-of-function mutations of GNRH1 gene are a very rare cause of autosomal recessive nCHH. R31C GNRH1 is the only missense mutation that affects the conserved GnRH de...

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Autores principales:	Luigi Maione, Frederique Albarel, Philippe Bouchard, Megan Gallant, Colleen A Flanagan, Regis Bobe, Joelle Cohen-Tannoudji, Rosario Pivonello, Annamaria Colao, Thierry Brue, Robert P Millar, Marc Lombes, Jacques Young, Anne Guiochon-Mantel, Jerome Bouligand
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a9255ab17ae24c32ade14102c14476b2
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spelling	oai:doaj.org-article:a9255ab17ae24c32ade14102c14476b22021-11-18T09:02:55ZR31C GNRH1 mutation and congenital hypogonadotropic hypogonadism.1932-620310.1371/journal.pone.0069616https://doaj.org/article/a9255ab17ae24c32ade14102c14476b22013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23936060/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Normosmic congenital hypogonadotropic hypogonadism (nCHH) is a rare reproductive disease leading to lack of puberty and infertility. Loss-of-function mutations of GNRH1 gene are a very rare cause of autosomal recessive nCHH. R31C GNRH1 is the only missense mutation that affects the conserved GnRH decapeptide sequence. This mutation was identified in a CpG islet in nine nCHH subjects from four unrelated families, giving evidence for a putative "hot spot". Interestingly, all the nCHH patients carry this mutation in heterozygosis that strikingly contrasts with the recessive inheritance associated with frame shift and non-sense mutations. Therefore, after exclusion of a second genetic event, a comprehensive functional characterization of the mutant R31C GnRH was undertaken. Using different cellular models, we clearly demonstrate a dramatic reduction of the mutant decapeptide capacity to bind GnRH-receptor, to activate MAPK pathway and to trigger inositol phosphate accumulation and intracellular calcium mobilization. In addition it is less able than wild type to induce lh-beta transcription and LH secretion in gonadotrope cells. Finally, the absence of a negative dominance in vitro offers a unique opportunity to discuss the complex in vivo patho-physiology of this form of nCHH.Luigi MaioneFrederique AlbarelPhilippe BouchardMegan GallantColleen A FlanaganRegis BobeJoelle Cohen-TannoudjiRosario PivonelloAnnamaria ColaoThierry BrueRobert P MillarMarc LombesJacques YoungAnne Guiochon-MantelJerome BouligandPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 7, p e69616 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Luigi Maione Frederique Albarel Philippe Bouchard Megan Gallant Colleen A Flanagan Regis Bobe Joelle Cohen-Tannoudji Rosario Pivonello Annamaria Colao Thierry Brue Robert P Millar Marc Lombes Jacques Young Anne Guiochon-Mantel Jerome Bouligand R31C GNRH1 mutation and congenital hypogonadotropic hypogonadism.
description	Normosmic congenital hypogonadotropic hypogonadism (nCHH) is a rare reproductive disease leading to lack of puberty and infertility. Loss-of-function mutations of GNRH1 gene are a very rare cause of autosomal recessive nCHH. R31C GNRH1 is the only missense mutation that affects the conserved GnRH decapeptide sequence. This mutation was identified in a CpG islet in nine nCHH subjects from four unrelated families, giving evidence for a putative "hot spot". Interestingly, all the nCHH patients carry this mutation in heterozygosis that strikingly contrasts with the recessive inheritance associated with frame shift and non-sense mutations. Therefore, after exclusion of a second genetic event, a comprehensive functional characterization of the mutant R31C GnRH was undertaken. Using different cellular models, we clearly demonstrate a dramatic reduction of the mutant decapeptide capacity to bind GnRH-receptor, to activate MAPK pathway and to trigger inositol phosphate accumulation and intracellular calcium mobilization. In addition it is less able than wild type to induce lh-beta transcription and LH secretion in gonadotrope cells. Finally, the absence of a negative dominance in vitro offers a unique opportunity to discuss the complex in vivo patho-physiology of this form of nCHH.
format	article
author	Luigi Maione Frederique Albarel Philippe Bouchard Megan Gallant Colleen A Flanagan Regis Bobe Joelle Cohen-Tannoudji Rosario Pivonello Annamaria Colao Thierry Brue Robert P Millar Marc Lombes Jacques Young Anne Guiochon-Mantel Jerome Bouligand
author_facet	Luigi Maione Frederique Albarel Philippe Bouchard Megan Gallant Colleen A Flanagan Regis Bobe Joelle Cohen-Tannoudji Rosario Pivonello Annamaria Colao Thierry Brue Robert P Millar Marc Lombes Jacques Young Anne Guiochon-Mantel Jerome Bouligand
author_sort	Luigi Maione
title	R31C GNRH1 mutation and congenital hypogonadotropic hypogonadism.
title_short	R31C GNRH1 mutation and congenital hypogonadotropic hypogonadism.
title_full	R31C GNRH1 mutation and congenital hypogonadotropic hypogonadism.
title_fullStr	R31C GNRH1 mutation and congenital hypogonadotropic hypogonadism.
title_full_unstemmed	R31C GNRH1 mutation and congenital hypogonadotropic hypogonadism.
title_sort	r31c gnrh1 mutation and congenital hypogonadotropic hypogonadism.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/a9255ab17ae24c32ade14102c14476b2
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R31C GNRH1 mutation and congenital hypogonadotropic hypogonadism.

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