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

Abstract

Context Mutations 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. 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 Sequencing of TAC3/TACR3; in vitro functional assays, neuroendocrine phenotyping. Setting Tertiary care centers world-wide. Patients or other participants 345 probands, 18 family members, 292 controls. Intervention Examination of reproductive phenotypes throughout reproductive life and pre/post therapy. Main Outcome Measure Rare sequence variants in TAC3/TACR3. Results In 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. Conclusions Mutations 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.

Neurokinin B Signalling in Human Puberty

“…Very recently, Gianetti et al. (15) reported mutations in 19 probands in TACR3 and in one multiplex family in TAC3 in a large population of 354 patients, indicating that TACR3 mutations are relatively common, at approximately 5%. Notably, as in the previous reported cases, the male subjects had microphallus.…”

Menstrual Cycle Disturbances at Reproductive Age

“…Topaloglu et al (2009) reported four human pedigrees with severe congenital gonadotropin deficiency and pubertal failure in which all affected individuals are homozygous for loss of function mutation in TAC3 (encoding neurokinin B) or its receptor TACR3 (encoding neurokinin B receptor). Gianetti et al (2010) presented phenotypic information concerning seven females with coding sequence variants in TACR3/TAC3. None of the females had spontaneous thelarche, and five of them demonstrated evidence for reversibility of their hypogonadism after discontinuation of therapy.…”