title: TAC3 and TACR3 defects cause hypothalamic congenital hypogonadotropic hypogonadism in humans.
abstract: BACKGROUND
  Missense loss-of-function mutations in TAC3 and TACR3, the genes encoding neurokinin B and its receptor NK3R, respectively, were recently discovered in kindreds with nonsyndromic normosmic congenital hypogonadotropic hypogonadism (CHH), thus identifying a fundamental role of this pathway in the human gonadotrope axis.
  
  
  OBJECTIVE
  The objective of the study was to investigate the consequences on gonadotrope axis of TAC3 deletion and TACR3 truncation in adult patients with normosmic complete CHH.
  
  
  RESULTS
  We identified three unrelated patients with the same homozygous substitution in the TAC3 intron 3 acceptor splicing site (c.209-1G>C) and three siblings who bore a homozygous mutation in the TACR3 intron 2 acceptor splicing site (c.738-1G>A). We demonstrated that these two mutations, respectively, deleted neurokinin B and truncated its receptor NK3R. We found in three patients with TAC3 mutation originating from Congo and Haiti a founding event in a more distant ancestor by means of haplotype analysis. We calculated that time to this common ancestor was approximately 21 generations. In several patients we observed a dissociation between the very low LH and normal or nearly normal FSH levels, this gonadotropin responding excessively to the GnRH challenge test. This particular hormonal profile, suggests the possibility of a specific neuroendocrine impairment in patients with alteration of neurokinin B signaling. Finally, in these patients, pulsatile GnRH administration normalized circulating sex steroids, LH release, and restored fertility in one subject.
  
  
  CONCLUSIONS
  Our data demonstrate the hypothalamic origin of the gonadotropin deficiency in these genetic forms of normosmic CHH. Neurokinin B and NK3R therefore both play a crucial role in hypothalamic GnRH release in humans.
authors.affiliation: Faculté de Médecine Paris-Sud, University Paris-Sud, INSERM Unité Mixte de Recherche S693, Le Kremlin Bicêtre, F-94276, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Young
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bouligand
authors.forename: Bruno
authors.initials: B
authors.lastname: Francou
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Raffin-Sanson
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Gaillez
authors.forename: Marc
authors.initials: M
authors.lastname: Jeanpierre
authors.forename: Michael
authors.initials: M
authors.lastname: Grynberg
authors.forename: Peter
authors.initials: P
authors.lastname: Kamenicky
authors.forename: Philippe
authors.initials: P
authors.lastname: Chanson
authors.forename: Sylvie
authors.initials: S
authors.lastname: Brailly-Tabard
authors.forename: Anne
authors.initials: A
authors.lastname: Guiochon-Mantel
mesh_terms: D000328:Adult; D000568:Amenorrhea / Q000235:genetics; D019943:Amino Acid Substitution; D001940:Breast / Q000254:growth & development; D003241:Consanguinity; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D017353:Gene Deletion; D006720:Homozygote; D006801:Humans; D007006:Hypogonadism / Q000235:genetics* / Q000503:physiopathology; D007438:Introns / Q000235:genetics; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D020125:Mutation, Missense; D015287:Neurokinin B / Q000235:genetics*; D010375:Pedigree; D010413:Penis / Q000002:abnormalities; D018042:Receptors, Neurokinin-3 / Q000235:genetics*; D013739:Testosterone / Q000097:blood
chemical_list: D018042:Receptors, Neurokinin-3; D013739:Testosterone; D015287:Neurokinin B; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone