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. PLoS One. 2013 Jul 25;8(7):e69616. doi: 10.1371/journal.pone.0069616. Print 2013.

Source

Université Paris-Sud, Faculté de Médecine Paris-Sud Unité mixte de Recherche en Santé 693, Le Kremlin Bicetre, France ; Service d'Endocrinologie et des Maladies de la Reproduction, Hopital Bicetre, Assistance Publique Hopitaux de Paris, Le Kremlin-Bicêtre, France ; Università degli Studi di Napoli Federico II, Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia e Metabolismo, Napoli, Italy.

Abstract

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.