ECE2013 Poster Presentations Male reproduction (41 abstracts)
Characterization of R31C GNRH1 mutation in congenital hypogonadotropic hypogonadism
Luigi Maione 1, , Frederique Albarel 3 , Philippe Bouchard 4 , Megan Gallant 5 , Colleen A Flanagan 5, , Regis Bobe 7 , Joelle Cohen-Tannoudji 9 , Rosario Pivonello 1 , Annamaria Colao 1 , Thierry Brue 3 , Marc Lombes 2 , Robert P Millar 5, , Jacques Young 2 , Anne Guiochon-Mantel 2 & Jerome Bouligand 2
1Università Federico II, Dipartimento di Endocrinologia ed Oncologia Clinica e Molecolare, Naples, Italy; 2Université Paris Sud, INSERM U693, Le Kremlin Bicetre, France; 3Département d’Endocrinologie et Centre de Référence des Maladies Rares d’Origine Hypophysaire, Hôpital de la Timone, Marseille, France; 4Service d’Endocrinologie, diabétologie et endocrinologie de la reproduction, Hôpital Saint-Antoine, Paris, France; 5UCT/MRC Receptor Biology Research Unit, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town Medical School, Cape Town, South Africa; 6Faculty of Health Sciences, School of Physiology, University of the Witwatersrand, Johannesburg, South Africa; 7Université Paris Sud, UMR-S770 INSERM, Le Kremlin Bicetre, France; 8Faculty of Natural and Agricultural Sciences, Mammal Research Institute, University of Pretoria, Pretoria, South Africa; 9Equipe Physiologie de l’Axe Gonadotrope, Unité de Biologie Fonctionnelle et Adaptative, CNRS-EAC 4413, Sorbonne Paris Cité, Université Paris Diderot-Paris 7, Paris, France.
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. We clearly demonstrate a dramatic reduction of the mutant decapeptide capacity to bind its cognate 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. Furthermore, the absence of a negative dominance in vitro offers a unique opportunity to discuss the complex in vivo pathophysiology of this apparently dominant form of nCHH.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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