期刊
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
卷 95, 期 6, 页码 2857-2867出版社
ENDOCRINE SOC
DOI: 10.1210/jc.2009-2320
关键词
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资金
- National Center for Research Resources (Harvard Clinical and Translational Science Center) [M01-RR-01066]
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [05/04726-0]
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) [300209/2008-8]
- Medical Research Council UK (MRC) [G0900567]
- European Commission
- Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health [U545U54HD028138]
- National Institutes of Health [R01-HD-42708]
- Medical Research Council [G0900567] Funding Source: researchfish
- MRC [G0900567] Funding Source: UKRI
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)
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