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Elena Gianetti, Cintia Tusset, Sekoni D. Noel, Margaret G. Au, Andrew A. Dwyer, Virginia A. Hughes, Ana Paula Abreu, Jessica Carroll, Ericka Trarbach, Leticia F. G. Silveira, Elaine M. F. Costa, Berenice Bilharinho de Mendonça, Margaret de Castro, Adriana Lofrano, Janet E. Hall, Erol Bolu, Metin Ozata, Richard Quinton, John K. Amory, Susan E. Stewart, Wiebke Arlt, Trevor R. Cole, William F. Crowley, Ursula B. Kaiser, Ana Claudia Latronico, Stephanie B. Seminara, TAC3/TACR3 Mutations Reveal Preferential Activation of Gonadotropin-Releasing Hormone Release by Neurokinin B in Neonatal Life Followed by Reversal in Adulthood, The Journal of Clinical Endocrinology & Metabolism, Volume 95, Issue 6, 1 June 2010, Pages 2857–2867, https://doi.org/10.1210/jc.2009-2320
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Abstract
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.
