Reference : TAC3 and TACR3 defects cause hypothalamic congenital hypogonadotropic hypogonadism in...
Scientific journals : Article
Life sciences : Genetics & genetic processes
TAC3 and TACR3 defects cause hypothalamic congenital hypogonadotropic hypogonadism in humans.
Young, Jacques [> > > >]
Bouligand, Jerome [> > > >]
Francou, Bruno [> > > >]
Raffin-Sanson, Marie*-Laure [> > > >]
Gaillez, Stephanie mailto [Centre Hospitalier Universitaire de Liège - CHU > > Génétique >]
Jeanpierre, Marc [> > > >]
Grynberg, Michael [> > > >]
Kamenicky, Peter [> > > >]
Chanson, Philippe [> > > >]
Brailly-Tabard, Sylvie [> > > >]
Guiochon-Mantel, Anne [> > > >]
Journal of Clinical Endocrinology and Metabolism
Endocrine Society
Yes (verified by ORBi)
Chevy Chase
[en] Adult ; Amenorrhea/genetics ; Amino Acid Substitution ; Breast/growth & development ; Consanguinity ; Female ; Follicle Stimulating Hormone/blood ; Gene Deletion ; Homozygote ; Humans ; Hypogonadism/genetics/physiopathology ; Introns/genetics ; Luteinizing Hormone/blood ; Male ; Mutation, Missense ; Neurokinin B/genetics ; Pedigree ; Penis/abnormalities ; Receptors, Neurokinin-3/genetics ; Testosterone/blood
[en] CONTEXT: 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. CONCLUSION: 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.

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