TAC3/TACR3 mutations reveal preferential activation of gonadotropin-releasing hormone release by neurokinin B in neonatal life followed by reversal in adulthood

J Clin Endocrinol Metab. 2010 Jun;95(6):2857-67. doi: 10.1210/jc.2009-2320. Epub 2010 Mar 23.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Amino Acid Sequence
  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Codon, Nonsense / genetics
  • DNA Mutational Analysis
  • Ethnic Groups
  • Female
  • Fertility / genetics
  • Genetic Variation
  • Gonadotropin-Releasing Hormone / metabolism*
  • Humans
  • Infant, Newborn
  • Male
  • Molecular Sequence Data
  • Mutation / physiology
  • Neurokinin B / genetics*
  • Neurokinin B / pharmacology*
  • Pedigree
  • Puberty / physiology
  • Receptors, Neurokinin-3 / genetics*
  • Receptors, Tachykinin / genetics*
  • Sex Characteristics
  • Tachykinins / genetics*
  • Transfection
  • Young Adult


  • Codon, Nonsense
  • Receptors, Neurokinin-3
  • Receptors, Tachykinin
  • Tachykinins
  • Gonadotropin-Releasing Hormone
  • Neurokinin B