Isolated familial hypogonadotropic hypogonadism and a GNRH1 mutation

Jerome Bouligand, Christina Ghervan, Javier Tello, Sylvie Brailly-Tabard, Sylvie Salenave, Philippe Chanson, Marc Lombes, Robert Millar, Anne Guiochon-Mantel

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231 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)2742-2748
Number of pages7
JournalNew England Journal of Medicine
Issue number26
Publication statusPublished - 25 Jun 2009


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