Normosmic congenital hypogonadotropic hypogonadism due to TAC3/TACR3 mutations: characterization of neuroendocrine phenotypes and novel mutations.

<h4>Context</h4>TAC3/TACR3 mutations have been reported in normosmic congenital hypogonadotropic hypogonadism (nCHH) (OMIM #146110). In the absence of animal models, studies of human neuroendocrine phenotypes associated with neurokinin B and NK3R receptor dysfunction can help to decipher...

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Autores principales: Bruno Francou, Jérôme Bouligand, Adela Voican, Larbi Amazit, Séverine Trabado, Jérôme Fagart, Geri Meduri, Sylvie Brailly-Tabard, Philippe Chanson, Pierre Lecomte, Anne Guiochon-Mantel, Jacques Young
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spelling oai:doaj.org-article:0226114bf1e34aec99ac309f4a828c5f2021-11-18T07:35:58ZNormosmic congenital hypogonadotropic hypogonadism due to TAC3/TACR3 mutations: characterization of neuroendocrine phenotypes and novel mutations.1932-620310.1371/journal.pone.0025614https://doaj.org/article/0226114bf1e34aec99ac309f4a828c5f2011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22031817/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Context</h4>TAC3/TACR3 mutations have been reported in normosmic congenital hypogonadotropic hypogonadism (nCHH) (OMIM #146110). In the absence of animal models, studies of human neuroendocrine phenotypes associated with neurokinin B and NK3R receptor dysfunction can help to decipher the pathophysiology of this signaling pathway.<h4>Objective</h4>To evaluate the prevalence of TAC3/TACR3 mutations, characterize novel TACR3 mutations and to analyze neuroendocrine profiles in nCHH caused by deleterious TAC3/TACR3 biallelic mutations.<h4>Results</h4>From a cohort of 352 CHH, we selected 173 nCHH patients and identified nine patients carrying TAC3 or TACR3 variants (5.2%). We describe here 7 of these TACR3 variants (1 frameshift and 2 nonsense deleterious mutations and 4 missense variants) found in 5 subjects. Modeling and functional studies of the latter demonstrated the deleterious consequence of one missense mutation (Tyr267Asn) probably caused by the misfolding of the mutated NK3R protein. We found a statistically significant (p<0.0001) higher mean FSH/LH ratio in 11 nCHH patients with TAC3/TACR3 biallelic mutations than in 47 nCHH patients with either biallelic mutations in KISS1R, GNRHR, or with no identified mutations and than in 50 Kallmann patients with mutations in KAL1, FGFR1 or PROK2/PROKR2. Three patients with TAC3/TACR3 biallelic mutations had an apulsatile LH profile but low-frequency alpha-subunit pulses. Pulsatile GnRH administration increased alpha-subunit pulsatile frequency and reduced the FSH/LH ratio.<h4>Conclusion</h4>The gonadotropin axis dysfunction associated with nCHH due to TAC3/TACR3 mutations is related to a low GnRH pulsatile frequency leading to a low frequency of alpha-subunit pulses and to an elevated FSH/LH ratio. This ratio might be useful for pre-screening nCHH patients for TAC3/TACR3 mutations.Bruno FrancouJérôme BouligandAdela VoicanLarbi AmazitSéverine TrabadoJérôme FagartGeri MeduriSylvie Brailly-TabardPhilippe ChansonPierre LecomteAnne Guiochon-MantelJacques YoungPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 10, p e25614 (2011)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Bruno Francou
Jérôme Bouligand
Adela Voican
Larbi Amazit
Séverine Trabado
Jérôme Fagart
Geri Meduri
Sylvie Brailly-Tabard
Philippe Chanson
Pierre Lecomte
Anne Guiochon-Mantel
Jacques Young
Normosmic congenital hypogonadotropic hypogonadism due to TAC3/TACR3 mutations: characterization of neuroendocrine phenotypes and novel mutations.
description <h4>Context</h4>TAC3/TACR3 mutations have been reported in normosmic congenital hypogonadotropic hypogonadism (nCHH) (OMIM #146110). In the absence of animal models, studies of human neuroendocrine phenotypes associated with neurokinin B and NK3R receptor dysfunction can help to decipher the pathophysiology of this signaling pathway.<h4>Objective</h4>To evaluate the prevalence of TAC3/TACR3 mutations, characterize novel TACR3 mutations and to analyze neuroendocrine profiles in nCHH caused by deleterious TAC3/TACR3 biallelic mutations.<h4>Results</h4>From a cohort of 352 CHH, we selected 173 nCHH patients and identified nine patients carrying TAC3 or TACR3 variants (5.2%). We describe here 7 of these TACR3 variants (1 frameshift and 2 nonsense deleterious mutations and 4 missense variants) found in 5 subjects. Modeling and functional studies of the latter demonstrated the deleterious consequence of one missense mutation (Tyr267Asn) probably caused by the misfolding of the mutated NK3R protein. We found a statistically significant (p<0.0001) higher mean FSH/LH ratio in 11 nCHH patients with TAC3/TACR3 biallelic mutations than in 47 nCHH patients with either biallelic mutations in KISS1R, GNRHR, or with no identified mutations and than in 50 Kallmann patients with mutations in KAL1, FGFR1 or PROK2/PROKR2. Three patients with TAC3/TACR3 biallelic mutations had an apulsatile LH profile but low-frequency alpha-subunit pulses. Pulsatile GnRH administration increased alpha-subunit pulsatile frequency and reduced the FSH/LH ratio.<h4>Conclusion</h4>The gonadotropin axis dysfunction associated with nCHH due to TAC3/TACR3 mutations is related to a low GnRH pulsatile frequency leading to a low frequency of alpha-subunit pulses and to an elevated FSH/LH ratio. This ratio might be useful for pre-screening nCHH patients for TAC3/TACR3 mutations.
format article
author Bruno Francou
Jérôme Bouligand
Adela Voican
Larbi Amazit
Séverine Trabado
Jérôme Fagart
Geri Meduri
Sylvie Brailly-Tabard
Philippe Chanson
Pierre Lecomte
Anne Guiochon-Mantel
Jacques Young
author_facet Bruno Francou
Jérôme Bouligand
Adela Voican
Larbi Amazit
Séverine Trabado
Jérôme Fagart
Geri Meduri
Sylvie Brailly-Tabard
Philippe Chanson
Pierre Lecomte
Anne Guiochon-Mantel
Jacques Young
author_sort Bruno Francou
title Normosmic congenital hypogonadotropic hypogonadism due to TAC3/TACR3 mutations: characterization of neuroendocrine phenotypes and novel mutations.
title_short Normosmic congenital hypogonadotropic hypogonadism due to TAC3/TACR3 mutations: characterization of neuroendocrine phenotypes and novel mutations.
title_full Normosmic congenital hypogonadotropic hypogonadism due to TAC3/TACR3 mutations: characterization of neuroendocrine phenotypes and novel mutations.
title_fullStr Normosmic congenital hypogonadotropic hypogonadism due to TAC3/TACR3 mutations: characterization of neuroendocrine phenotypes and novel mutations.
title_full_unstemmed Normosmic congenital hypogonadotropic hypogonadism due to TAC3/TACR3 mutations: characterization of neuroendocrine phenotypes and novel mutations.
title_sort normosmic congenital hypogonadotropic hypogonadism due to tac3/tacr3 mutations: characterization of neuroendocrine phenotypes and novel mutations.
publisher Public Library of Science (PLoS)
publishDate 2011
url https://doaj.org/article/0226114bf1e34aec99ac309f4a828c5f
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