TAC3/TACR3 Mutations Reveal Preferential Activation of GnRH Release by Neurokinin B in Neonatal Life Followed by Reversal in Adulthood

• Published in: Endocrine reviews 2010-04, Vol.31 (2), p.254-255
• Main Authors: Gianetti, Elena, Tusset, Cintia, Noel, Sekoni D, Au, Margaret G, Dwyer, Andrew A, Hughes, Virginia A, Abreu, Ana Paula, Carroll, Jessica, Trarbach, Ericka, Silveira, Leticia FG, Costa, Elaine MF, de Mendonça, Berenice Bilharinho, de Castro, Margaret, Lofrano, Adriana, Hall, Janet E, Bolu, Erol, Ozata, Metin, Quinton, Richard, Amory, John K, Stewart, Susan E, Arlt, Wiebke, Cole, Trevor R, Crowley, William F, Kaiser, Ursula B, Latronico, Ana Claudia, Seminara, Stephanie B
• Format: Article
• Language: English
• Subjects: Coding; Females; Gene deletion; Genotypes; Gonadotropin-releasing hormone; Hypogonadism; Hypothalamic-pituitary-gonadal axis; Hypothalamus; Males; Mutation; Neonates; Neural coding; Neurokinin; Neurokinin B; Nonsense mutation; Nucleotides; Phenotypes; Phenotyping; Pituitary; Pituitary-gonadal axis
• ISSN: 0163-769X; 1945-7189
• DOI: 10.1210/edrv.31.2.9979

ContextMutations in TAC3 and TACR3 (encoding neurokinin B and its receptor) have been identified in Turkish patients with hypogonadotropic hypogonadism (IHH), but broader populations have not yet been tested and genotype-phenotype correlations have not been established.ObjectiveA 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.DesignSequencing of TAC3/TACR3; in vitro functional assays, neuroendocrine phenotyping.SettingTertiary care centers world-wide.Patients or other participants345 probands, 18 family members, 292 controls.InterventionExamination of reproductive phenotypes throughout reproductive life and pre/post therapy.Main Outcome MeasureRare sequence variants in TAC3/TACR3.ResultsIn TACR3, 19 probands harbored 13 distinct coding sequence rare nucleotide variants (3 nonsense mutations, 6 non-synonymous, 4 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 7 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 5/7 females were assessed after discontinuation of therapy and 6/7 males and 4/5 females demonstrated evidence for reversibility of their hypogonadotropism.ConclusionsMutations in the neurokinin B pathway are relatively common as causes of hypogonadism. While 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.