title: Isolated familial hypogonadotropic hypogonadism and a GNRH1 mutation.
abstract: 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.
authors.affiliation: Université Paris-Sud, Faculté de Médecine Paris-Sud and Assistance Publique-Hôpitaux de Paris, Hôpital de Bicêtre, INSERM UMR-S693, Paris, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bouligand
authors.forename: Cristina
authors.initials: C
authors.lastname: Ghervan
authors.forename: Javier A
authors.initials: JA
authors.lastname: Tello
authors.forename: Sylvie
authors.initials: S
authors.lastname: Brailly-Tabard
authors.forename: Sylvie
authors.initials: S
authors.lastname: Salenave
authors.forename: Philippe
authors.initials: P
authors.lastname: Chanson
authors.forename: Marc
authors.initials: M
authors.lastname: Lombès
authors.forename: Robert P
authors.initials: RP
authors.lastname: Millar
authors.forename: Anne
authors.initials: A
authors.lastname: Guiochon-Mantel
authors.forename: Jacques
authors.initials: J
authors.lastname: Young
mesh_terms: D000293:Adolescent; D004958:Estradiol / Q000097:blood; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D016368:Frameshift Mutation; D005808:Genes, Recessive; D007987:Gonadotropin-Releasing Hormone / Q000008:administration & dosage / Q000172:deficiency / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007006:Hypogonadism / Q000235:genetics*; D007986:Luteinizing Hormone / Q000097:blood / Q000378:metabolism; D008297:Male; D010375:Pedigree; D011498:Protein Precursors / Q000235:genetics*; D017422:Sequence Analysis, DNA; D013739:Testosterone / Q000097:blood
chemical_list: D011498:Protein Precursors; C050866:progonadoliberin I; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D004958:Estradiol; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone