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...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2013-01-01
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| Series: | PLoS ONE |
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23936060/pdf/?tool=EBI |
| _version_ | 1818460873310601216 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-14T23:37:10Z |
| format | Article |
| id | doaj.art-a9255ab17ae24c32ade14102c14476b2 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-14T23:37:10Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-a9255ab17ae24c32ade14102c14476b22022-12-21T22:43:36ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0187e6961610.1371/journal.pone.0069616R31C GNRH1 mutation and congenital hypogonadotropic hypogonadism.Luigi MaioneFrederique AlbarelPhilippe BouchardMegan GallantColleen A FlanaganRegis BobeJoelle Cohen-TannoudjiRosario PivonelloAnnamaria ColaoThierry BrueRobert P MillarMarc LombesJacques YoungAnne Guiochon-MantelJerome BouligandNormosmic 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.https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23936060/pdf/?tool=EBI |
| spellingShingle | 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. PLoS ONE |
| title | 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_short | R31C GNRH1 mutation and congenital hypogonadotropic hypogonadism. |
| title_sort | r31c gnrh1 mutation and congenital hypogonadotropic hypogonadism |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23936060/pdf/?tool=EBI |
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