TAC3/TACR3 Mutations Reveal Preferential Activation of Gonadotropin-Releasing Hormone Release by Neurokinin B in Neonatal Life Followed by Reversal in Adulthood
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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DOI：
10.1210/jc.2009-2320
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发表时间：
2010-06-01
影响因子：
5.8
通讯作者：
Seminara, Stephanie B.
中科院分区：
文献类型：
--
作者：
Gianetti, Elena;Tusset, Cintia;Seminara, Stephanie B.
内容：TAC 3和TACR 3的突变（编码神经激肽B及其受体）已在土耳其特发性低促性腺激素性性腺功能减退症（IHH）患者中被鉴定，但尚未对更广泛的人群进行测试，并且尚未建立基因型-表型相关性。对一个广泛的正常嗅觉IHH先证者队列进行TAC 3/TACR 3突变筛查，以评估此类突变的患病率并确定基因型。设计和设置：该研究包括TAC 3/TACR 3的测序、体外功能测定和在世界范围内的三级护理中心进行的神经内分泌表型分析。在整个生育期和治疗前后检测生殖表型。主要结果测量：检测到TAC 3/TACR 3中的罕见序列变异。在TACR 3中，19名先证者携带13种不同的编码序列罕见核苷酸变异[3种无义突变，6种非同义突变，4种同义突变（1种预测影响剪接）]。在TAC 3中，鉴定了一个纯合的单碱基对缺失，导致神经激肽B十肽完全缺失。在TACR 3/TAC 3编码序列变异的16只雄性和7只雌性中获得了表型信息。在16名男性中，15名有小阴茎;没有女性有自发性乳房发育。7的16名男性和5的7名女性进行了评估后，停止治疗; 6的7名男性和4的5名女性表现出证据的可逆性，他们的hypogonadotrophicity.Conclusions：在神经激肽B通路的突变是比较常见的原因性腺功能减退症。虽然神经激肽B通路在早期性发育过程中是必不可少的，但它在维持下丘脑-垂体-性腺轴完整性方面的重要性似乎随着时间的推移而减弱。（临床内分泌代谢杂志95：2857-2867，2010）
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)