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Previous Volume 360:2742-2748 June 25, 2009 Number 26 Next

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SUMMARY

We investigated whether mutations in the gene encoding gonadotropin-releasing hormone 1 (GNRH1) might be responsible for idiopathic hypogonadotropic hypogonadism (IHH) in humans. We identified a homozygous GNRH1 frameshift mutation, an insertion of an adenine at nucleotide position 18 (c.18-19insA), in the sequence encoding the N-terminal region of the signal peptide–containing protein precursor of gonadotropin-releasing hormone (prepro-GnRH) in a teenage brother and sister, who had normosmic IHH. Their unaffected parents and a sibling who was tested were heterozygous. This mutation results in an aberrant peptide lacking the conserved GnRH decapeptide sequence, as shown by the absence of immunoreactive GnRH when expressed in vitro. This isolated autosomal recessive GnRH deficiency, reversed by pulsatile GnRH administration, shows the pivotal role of GnRH in human reproduction.

Source Information

From Université Paris-Sud, Faculté de Médecine Paris-Sud and Assistance Publique–Hôpitaux de Paris, Hôpital de Bicêtre, INSERM UMR-S693, Paris (J.B., S.B.-T., P.C., M.L., A.G.-M., J.Y.); Laboratoire de Génétique Moléculaire, Pharmacogénétique et Hormonologie (J.B., S.B.-T., A.G.-M.), and Service d'Endocrinologie et des Maladies de la Reproduction and Centre de Référence des Maladies Endocriniennes Rares de la Croissance (S.S., P.C., M.L., J.Y.) — all in Le Kremlin-Bicêtre, France; the Endocrinology Department, University of Medicine and Pharmacy Iuliu Hatieganu, Cluj-Napoca, Romania (C.G.); the Medical Research Council Human Reproductive Sciences Unit, the Queen's Medical Research Institute, Edinburgh (J.A.T., R.P.M.); and the Research Group for Receptor Biology, Division of Medical Biochemistry, University of Cape Town, Cape Town, South Africa (R.P.M.).

Drs. Bouligand and Ghervan and Drs. Guiochon-Mantel and Young contributed equally to this article.

This article (10.1056/NEJMoa0900136) was published on June 17, 2009, at NEJM.org.

Address reprint requests to Dr. Young at the Service d'Endocrinologie et des Maladies de la Reproduction, Hôpital de Bicêtre, 78 Rue du Général Leclerc, 94275 Le Kremlin-Bicêtre, France, or at jacques.young{at}bct.aphp.fr.

Full Text of this Article

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