TAC3/TACR3 Mutations Reveal Preferential Activation of Gonadotropin-Releasing Hormone Release by Neurokinin B in Neonatal Life Followed by Reversal in Adulthood

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Gianetti, Elena ^{[1, 2]} ; Tusset, Cintia ^[3] ; Noel, Sekoni D. ^{[4, 5, 6]} ; Au, Margaret G. ^{[1, 2]} ; Dwyer, Andrew A. ^{[1, 2]} ; Hughes, Virginia A. ^{[1, 2]} ; Abreu, Ana Paula ^{[4, 5, 6]} ; Carroll, Jessica ^{[4, 5, 6]} ; Trarbach, Ericka ^[3] ; Silveira, Leticia F. G. ; Costa, Elaine M. F. ^[3] ; de Mendonca, Berenice Bilharinho ^[3] ; de Castro, Margaret ^[7] ; Lofrano, Adriana ^{[8, 9]} ; Hall, Janet E. ^{[1, 2]} ; Bolu, Erol ^[10] ; Ozata, Metin ^[10] ; Quinton, Richard ^[11] ; Amory, John K. ^[12] ; Stewart, Susan E. ^[13] ; Arlt, Wiebke ; Cole, Trevor R. ^[13] ; Crowley, William F. ^{[1, 2, 14]} ; Kaiser, Ursula B. ^{[4, 5, 6]} ; Latronico, Ana Claudia ^[3] ; Seminara, Stephanie B. ^{[1, 2]}

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^[1] Massachusetts Gen Hosp, Dept Med, Reprod Endocrine Unit, Boston, MA 02114 - USA

^[2] Massachusetts Gen Hosp, Dept Med, Harvard Ctr Reprod Sci, Boston, MA 02114 - USA

^[3] Univ Sao Paulo, Lab Hormonios & Genet Mol, Serv Endocrinol, Div Clin Med 1, Hosp Clin, Fac Med, BR-05403900 Sao Paulo - Brazil

^[4] Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 - USA

^[5] Harvard Univ, Sch Med, Boston, MA 02115 - USA

^[6] Brigham & Womens Hosp, Harvard Ctr Reprod Sci, Boston, MA 02115 - USA

^[7] Univ Sao Paulo, Dept Clin Med, Fac Med Ribeirao Preto, BR-14049900 Sao Paulo - Brazil

^[8] Univ Hosp Brasilia, Endocrinol Sect, BR-70910900 Brasilia, DF - Brazil

^[9] Univ Brasilia, Mol Pharmacol Lab, Fac Hlth Sci, BR-70910900 Brasilia, DF - Brazil

^[10] Gulhane Mil Med Acad, Dept Endocrinol, TR-06018 Ankara - Turkey

^[11] Newcastle Univ, Inst Human Genet, Endocrinol Res Grp, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear - England

^[12] Univ Washington, Med Ctr, Div Gen Internal Med, Seattle, WA 98195 - USA

^[13] Birmingham Womens Hosp Natl Hlth Serv Fdn Trust, Genet Unit, Birmingham B15 2TG, W Midlands - England

^[14] Univ Birmingham, Sch Clin & Expt Med, Ctr Endocrinol Diabet & Metab, Birmingham B15 2TT, W Midlands - England

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; v. 95, n. 6, p. 2857-2867, JUN 2010.
• Citações Web of Science: 134

Resumo

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. (J Clin Endocrinol Metab 95: 2857-2867, 2010) (AU)

• Processo FAPESP: 05/04726-0 - Caracterização molecular das doenças endócrinas congênitas que afetam o crescimento e o desenvolvimento
• Beneficiário: Ana Claudia Latronico Xavier
• Modalidade de apoio: Auxílio à Pesquisa - Temático