TAC3/TACR3 mutations reveal preferential activation of gonadotropin-releasing hormone release by neurokinin B in neonatal life followed by reversal in adulthood
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CONTEXT: Mutations in TAC3 and TACR3 (encoding neurokinin B and its receptor) have been identified in Turkish patients with idiopathic hypogonadotropic hypogonadism (IHH), but broader populations have not yet been tested and genotype-phenotype correlations have not been established. OBJECTIVE: A broad cohort of normosmic IHH probands was screened for mutations in TAC3/TACR3 to evaluate the prevalence of such mutations and define the genotype/phenotype relationships. DESIGN AND SETTING: The study consisted of sequencing of TAC3/TACR3, in vitro functional assays, and neuroendocrine phenotyping conducted in tertiary care centers worldwide. PATIENTS OR OTHER PARTICIPANTS: 345 probands, 18 family members, and 292 controls were studied. INTERVENTION: Reproductive phenotypes throughout reproductive life and before and after therapy were examined. MAIN OUTCOME MEASURE: Rare sequence variants in TAC3/TACR3 were detected. RESULTS: In TACR3, 19 probands harbored 13 distinct coding sequence rare nucleotide variants [three nonsense mutations, six nonsynonymous, four synonymous (one predicted to affect splicing)]. In TAC3, one homozygous single base pair deletion was identified, resulting in complete loss of the neurokinin B decapeptide. Phenotypic information was available on 16 males and seven females with coding sequence variants in TACR3/TAC3. Of the 16 males, 15 had microphallus; none of the females had spontaneous thelarche. Seven of the 16 males and five of the seven females were assessed after discontinuation of therapy; six of the seven males and four of the five females demonstrated evidence for reversibility of their hypogonadotropism. CONCLUSIONS: Mutations in the neurokinin B pathway are relatively common as causes of hypogonadism. Although the neurokinin B pathway appears essential during early sexual development, its importance in sustaining the integrity of the hypothalamic-pituitary-gonadal axis appears attenuated over time.
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The report by Gianetti and colleagues of reversibility of isolated hypogonadotropic hypogonadism in a high proportion of patients with TACR3 mutations suggested that the NKB system is not absolutely required for GnRH regulation after the maturation of the hypothalamic-pituitary-gonadal axis.
“The report by Gianetti and colleagues63 of reversibility of isolated hypogonadotropic hypogonadism in a high proportion of patients with TACR3 mutations suggested that the NKB system is not absolutely required for GnRH regulation after the maturation of the hypothalamic-pituitary-gonadal axis.”
From Pubertal development and regulation (2016) · cites this paper as [63]
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 Gianetti et al., 2010
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- Authors
- Gianetti, E., Tusset, C., Noel, S. D., Au, M. G., Dwyer, A. A., Hughes, V. A., Abreu, A. P., Carroll, J., Trarbach, E., Silveira, L. F. G., Costa, E. M. F., de Mendonça, B. B., de Castro, M., Lofrano, A., Hall, J. E., Bolu, E., Ozata, M., Quinton, R., Amory, J. K., Stewart, S. E., Arlt, W., Cole, T. R., Crowley, W. F., Kaiser, U. B., Latronico, A. C., & Seminara, S. B.
- Affiliations
- Harvard University (US)
- Laboratório de Hormônios e Genética Molecular (C.T., E.T., L.F.G.S., E.M.F.C., B.B.d.M., A.C.L.), Serviço de Endocrinologia - Divisão de Clínica Médica I, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo 05403-900 São Paulo, Brazil
- Brigham and Women's Hospital (US)
- Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (BR)
- Departamento de Clínica Médica (M.d.C.), Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, Monte Alegre 14049900 Ribeirao Preto, Sao Paulo, Brazil
- Section of Endocrinology (A.L.), University Hospital of Brasilia and Molecular Pharmacology Laboratory, Faculty of Health Sciences, University of Brasilia, DF 70910-900 Brasilia, Brazil
- Department of Endocrinology (E.B., M.O.), Gulhane School of Medicine, Ankara 06018, Turkey
- Newcastle University (GB)
- University of Washington Medical Center (US)
- National Health Service (GB)
- University of Birmingham (GB)
- Corresponding author
- Seminara, Stephanie B.
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2010-06-01
- Volume
- 95
- Issue
- 6
- Pages
- 2857-2867
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC2902066
- OpenAlex
- W2053608443
- Cited by
- 294
- References
- 41
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 6 · 2023: 12 · 2022: 18 · 2021: 22 · 2020: 14 · 2019: 15 · 2018: 20 · 2017: 10 · 2016: 27 · 2015: 25 · 2014: 25 · 2013: 20 · 2012: 21
- FWCI
- 32.25
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Scientific Electronic Library Online (São Paulo Research Foundation, Latin American and Caribbean Center on Health Sciences Information, Conselho Nacional de Desenvolvimento Científico e Tecnológico) (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- Medical Research Council (G0900567)
- National Institute of Horticultural and Herbal Science, Rural Development Administration
- National Center for Research Resources (M01RR001066, M01-RR01066)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD 42708, R01HD043341, R01HD042708, U54HD028138)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
- Keywords
- TAC3, TACR3, neurokinin B, idiopathic hypogonadotropic hypogonadism, genotype-phenotype correlation, rare variants, micropenis, hypothalamic-pituitary-gonadal axis
- MeSH terms
- Adolescent, Adult, Amino Acid Sequence, Animals, Chlorocebus aethiops, DNA Mutational Analysis, Ethnicity, Female, Fertility, Humans, Infant, Newborn, Gonadotropin-Releasing Hormone, Male, Molecular Sequence Data, Mutation, Pedigree, Puberty, Sex Characteristics, Transfection, Genetic Variation, Neurokinin B, Tachykinins, Receptors, Tachykinin, Receptors, Neurokinin-3, Codon, Nonsense, COS Cells, Young Adult
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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