Maione, LuigiAlbarel, FrederiqueBouchard, PhilippeGallant, MeganFlanagan, Colleen A.Bobe, RegisCohen-Tannoudji, JoellePivonello, RosarioColao, AnnamariaBrue, ThierryMillar, Robert P.Lombes, MarcYoung, JacquesGuiochon-Mantel, AnneBouligand, Jerome2013-10-082013-10-082013-07-25Maione L, Albarel F, Bouchard P, Gallant M, Flanagan CA, et al. (2013) R31C GNRH1 Mutation and Congenital Hypogonadotropic Hypogonadism. PLoS ONE 8(7): e69616. DOI: 10.1371/journal.pone.00696161932-620310.1371/journal.pone.0069616http://hdl.handle.net/2263/31938Normosmic 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 lhbeta 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.en© 2013 Maione et al. This is an open-access article distributed under the terms of the Creative Commons Attribution LicenseGNRH1 geneNormosmic congenital hypogonadotropic hypogonadism (nCHH)Gonadotropin-releasing hormone (GnRH)MutationArticle