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

被引:196
作者
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 ]
机构
[1] Massachusetts Gen Hosp, Dept Med, Harvard Ctr Reprod Sci, Boston, MA 02114 USA
[2] Massachusetts Gen Hosp, Dept Med, Reprod Endocrine Unit, 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, Harvard Ctr Reprod Sci, Boston, MA 02115 USA
[5] Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 USA
[6] Harvard Univ, Sch Med, 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
基金
巴西圣保罗研究基金会; 英国医学研究理事会; 美国国家卫生研究院;
关键词
IDIOPATHIC HYPOGONADOTROPIC HYPOGONADISM; GENE; DEFICIENCY; RECEPTOR; PROKINETICIN-2; HETEROGENEITY; SECRETION; NEURONS; PATIENT; PROTEIN;
D O I
10.1210/jc.2009-2320
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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)
引用
收藏
页码:2857 / 2867
页数:11
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