• PMID: 23936060
• Gene Name: GNRH1
• Condition: Congenital hypogonadotropic hypogonadism
• Association: 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".
• Mutation: R31C GNRH1
• Population size: 9
• Population details: 9 nCHH subjects
• Sex: Mae, female
• Infertility type: Male infertility, Female infertility
• Other associated phenotypes: Congenital hypogonadotropic hypogonadism

R31C GNRH1 mutation and congenital hypogonadotropic hypogonadism

Maione L, Albarel F, Bouchard P, Gallant M, Flanagan CA, Bobe R, Cohen-Tannoudji J, Pivonello R, Colao A, Brue T, Millar RP, Lombes M, Young J, Guiochon-Mantel A, Bouligand J.

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. FAU - Maione, Luigi AU - Maione L AD - Université Paris-Sud, Faculté de Médecine Paris-Sud Unité mixte de Recherche en Santé 693, Le Kremlin Bicetre, France. FAU - Albarel, Frederique AU - Albarel F FAU - Bouchard, Philippe AU - Bouchard P FAU - Gallant, Megan AU - Gallant M FAU - Flanagan, Colleen A AU - Flanagan CA FAU - Bobe, Regis AU - Bobe R FAU - Cohen-Tannoudji, Joelle AU - Cohen-Tannoudji J FAU - Pivonello, Rosario AU - Pivonello R FAU - Colao, Annamaria AU - Colao A FAU - Brue, Thierry AU - Brue T FAU - Millar, Robert P AU - Millar RP FAU - Lombes, Marc AU - Lombes M FAU - Young, Jacques AU - Young J FAU - Guiochon-Mantel, Anne AU - Guiochon-Mantel A