TAC3 and TACR3 Defects Cause Hypothalamic Congenital Hypogonadotropic Hypogonadism in Humans
Abstract
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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Individuals with mutations in the genes encoding NKB or its receptor NK3R are infertile and do not transition through puberty.
“The significance of this line of inquiry became apparent with the discovery that individuals with mutations in the genes encoding NKB or its receptor (NK3R) are infertile and do not transition through puberty (Gianetti et al., 2010; Topaloglu et al., 2009; Young et al., 2010).”
From Modulation of body temperature and LH secretion by hypothalamic KNDy (kisspeptin, neurokinin B and dynorphin) neurons: A novel hypothesis on the mechanism of hot flushes (2013) · cites this paper as Young et al., 2010
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- Authors
- Young, J., Bouligand, J., Francou, B., Raffin-Sanson, M.-L., Gaillez, S., Jeanpierre, M., Grynberg, M., Kamenicky, P., Chanson, P., Brailly-Tabard, S., & Guiochon-Mantel, A.
- Affiliations
- Université Paris-Sud (FR)
- Faculté de Médecine Paris-Sud (J.Y., J.B., B.F., M.G., P.K., P.C., S.B.-T., A.G.-M.), University Paris-Sud, INSERM Unité Mixte de Recherche S693, Le Kremlin Bicêtre, F-94276, France
- Service d’Endocrinologie (M.-L.R.-S.), Hôpital Ambroise Paré, Assistance Publique-Hôpitaux de Paris F-92100 Boulogne-Billancourt, France
- Centre de Génétique Humaine (S.G.), Liège, Belgique
- Inserm (FR)
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2010-05-01
- Volume
- 95
- Issue
- 5
- Pages
- 2287-2295
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2022586856
- Semantic Scholar
- 1878d3c1db4be750dc51ed8a618564cb4a53c349
- Cited by
- 249
- References
- 23
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 11 · 2023: 13 · 2022: 11 · 2021: 11 · 2020: 13 · 2019: 13 · 2018: 13 · 2017: 14 · 2016: 19 · 2015: 18 · 2014: 29 · 2013: 19 · 2012: 23
- FWCI
- 26.18
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- ORBi (University of Liège) (submittedVersion)
- Funders
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Fondation pour la Recherche Médicale
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Keywords
- congenital hypogonadotropic hypogonadism, TAC3, TACR3, neurokinin B, NK3 receptor, gonadotropin deficiency, LH deficiency, follicle-stimulating hormone, pulsatile GnRH therapy, founder mutation, haplotype analysis, fertility restoration, sex hormone deficiency
- MeSH terms
- Adult, Amenorrhea, Breast, Consanguinity, Female, Follicle Stimulating Hormone, Homozygote, Humans, Hypogonadism, Introns, Luteinizing Hormone, Male, Pedigree, Penis, Testosterone, Neurokinin B, Gene Deletion, Receptors, Neurokinin-3, Amino Acid Substitution, Mutation, Missense
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