R31C GNRH1 mutation and congenital hypogonadotropic hypogonadism

• Published in: PloS one 2013-07, Vol.8 (7), p.e69616-e69616
• Main Authors: Maione, Luigi, Albarel, Frederique, Bouchard, Philippe, Gallant, Megan, Flanagan, Colleen A, Bobe, Regis, Cohen-Tannoudji, Joelle, Pivonello, Rosario, Colao, Annamaria, Brue, Thierry, Millar, Robert P, Lombes, Marc, Young, Jacques, Guiochon-Mantel, Anne, Bouligand, Jerome
• Format: Article
• Language: English
• Subjects: Aged; Amino Acid Sequence; Amino acids; Base Sequence; Biology; Calcium; Calcium (intracellular); Calcium - metabolism; Calcium mobilization; Calcium phosphates; Cell Line; Congenital diseases; Conserved sequence; Councils; CpG Islands; Endocrinology; Female; Gene Expression Regulation; Genetic aspects; Genetic disorders; Gonadotrophs - metabolism; Gonadotrophs - pathology; Gonadotropin-releasing hormone; Gonadotropin-Releasing Hormone - genetics; Gonadotropin-Releasing Hormone - metabolism; Heredity; Heterozygote; Hot spots; Humans; Hypogonadism; Hypogonadism - congenital; Hypogonadism - genetics; Hypogonadism - physiopathology; Infectious diseases; Infertility; Inositol phosphate; Inositol Phosphates - metabolism; Luteinizing hormone; Luteinizing Hormone, beta Subunit - genetics; Luteinizing Hormone, beta Subunit - metabolism; Male; Mammals; MAP kinase; MAP Kinase Signaling System; Mathematics; Medical research; Medicine; Missense mutation; Molecular Sequence Data; Mutation; Mutation, Missense; Neurohormones; Observatories; Pedigree; Phosphates; Physiology; Pituitary (anterior); Protein Binding; Protein Precursors - genetics; Protein Precursors - metabolism; Puberty; Receptors, LHRH - genetics; Receptors, LHRH - metabolism; Secretion; Transcription; Young Adult
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0069616

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.