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- Title
TAC3/TACR3 mutations reveal preferential activation of gonadotropin-releasing hormone release by neurokinin B in neonatal life followed by reversal in adulthood.
- 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 F G; Costa, Elaine M F; de Mendonça, Berenice Bilharinho; de Castro, Margaret; Lofrano, Adriana; Hall, Janet E; Bolu, Erol; Ozata, Metin; Quinton, Richard; Amory, John K; Stewart, Susan E
- Abstract
<bold>Context: </bold>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.<bold>Objective: </bold>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.<bold>Design and Setting: </bold>The study consisted of sequencing of TAC3/TACR3, in vitro functional assays, and neuroendocrine phenotyping conducted in tertiary care centers worldwide.<bold>Patients or Other Participants: </bold>345 probands, 18 family members, and 292 controls were studied.<bold>Intervention: </bold>Reproductive phenotypes throughout reproductive life and before and after therapy were examined.<bold>Main Outcome Measure: </bold>Rare sequence variants in TAC3/TACR3 were detected.<bold>Results: </bold>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.<bold>Conclusions: </bold>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.
- Subjects
AMINO acids; CELL receptors; DOCUMENTATION; DRUGS; ETHNIC groups; FERTILITY; GENEALOGY; GENETICS; GENETIC techniques; HUMAN reproduction; GONADOTROPIN releasing hormone; GENETIC mutation; NEUROTRANSMITTERS; PRIMATES; PUBERTY; RESEARCH funding; SEQUENCE analysis; PHARMACODYNAMICS
- Publication
Journal of Clinical Endocrinology & Metabolism, 2010, Vol 95, Issue 6, p2857
- ISSN
0021-972X
- Publication type
journal article
- DOI
10.1210/jc.2009-2320