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

AbstractCONTEXT:
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.
AuthorsElena 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
JournalThe Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 95 Issue 6 Pg. 2857-67 (Jun 2010) ISSN: 1945-7197 [Electronic] United States
PMID20332248 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Codon, Nonsense
  • Receptors, Neurokinin-3
  • Receptors, Tachykinin
  • Tachykinins
  • Gonadotropin-Releasing Hormone
  • Neurokinin B
Topics
  • Adolescent
  • Adult
  • Amino Acid Sequence
  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Codon, Nonsense (genetics)
  • DNA Mutational Analysis
  • Ethnicity
  • Female
  • Fertility (genetics)
  • Genetic Variation
  • Gonadotropin-Releasing Hormone (metabolism)
  • Humans
  • Infant, Newborn
  • Male
  • Molecular Sequence Data
  • Mutation (physiology)
  • Neurokinin B (genetics, pharmacology)
  • Pedigree
  • Puberty (physiology)
  • Receptors, Neurokinin-3 (genetics)
  • Receptors, Tachykinin (genetics)
  • Sex Characteristics
  • Tachykinins (genetics)
  • Transfection
  • Young Adult

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