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

来源：

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM | 2010年 / 95卷 / 06期

基金：

巴西圣保罗研究基金会; 美国国家卫生研究院; 英国医学研究理事会;

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

页码：2857 / 2867

页数：11

共 36 条

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