R31C GNRH1 mutation and congenital hypogonadotropic hypogonadism

Luigi Maione; Frederique Albarel; Philippe Bouchard; Megan Gallant; Colleen A Flanagan; Regis Bobe; Joelle Cohen-Tannoudji; Rosario Pivonello; Annamaria Colao; Thierry Brue; Robert P Millar; Marc Lombes; Jacques Young; Anne Guiochon-Mantel; Jerome Bouligand

doi:10.1371/journal.pone.0069616

R31C GNRH1 mutation and congenital hypogonadotropic hypogonadism

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

Authors

Luigi Maione¹, Frederique Albarel, Philippe Bouchard, Megan Gallant, Colleen A Flanagan, Regis Bobe, Joelle Cohen-Tannoudji, Rosario Pivonello, Annamaria Colao, Thierry Brue, Robert P Millar, Marc Lombes, Jacques Young, Anne Guiochon-Mantel, Jerome Bouligand

Affiliation

¹ Université Paris-Sud, Faculté de Médecine Paris-Sud Unité mixte de Recherche en Santé 693, Le Kremlin Bicetre, France.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Amino Acid Sequence
Base Sequence
Calcium / metabolism
Cell Line
CpG Islands
Female
Gene Expression Regulation
Gonadotrophs / metabolism
Gonadotrophs / pathology
Gonadotropin-Releasing Hormone / genetics*
Gonadotropin-Releasing Hormone / metabolism
Heterozygote
Humans
Hypogonadism / congenital
Hypogonadism / genetics*
Hypogonadism / physiopathology
Inositol Phosphates / metabolism
Luteinizing Hormone, beta Subunit / genetics*
Luteinizing Hormone, beta Subunit / metabolism
MAP Kinase Signaling System
Male
Molecular Sequence Data
Mutation, Missense*
Pedigree
Protein Binding
Protein Precursors / genetics*
Protein Precursors / metabolism
Receptors, LHRH / genetics*
Receptors, LHRH / metabolism
Young Adult

Substances

Inositol Phosphates
Luteinizing Hormone, beta Subunit
Protein Precursors
Receptors, LHRH
progonadoliberin I
Gonadotropin-Releasing Hormone
Calcium

Grants and funding

This work was supported in part by grants from Paris-Sud 11 University (Bonus Qualité Recherche 2009, Attractivité Univ. Paris Sud 2010), PHRC HYPOPROTEO P081212 and Fondation pour la Recherche Médicale. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.