A genetic basis for functional hypothalamic amenorrhea.
A genetic basis for functional hypothalamic amenorrhea.
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DOI：
10.1056/nejmoa0911064
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发表时间：
2011-01-20
期刊：
影响因子：
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通讯作者：
Pitteloud N
中科院分区：
文献类型：
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作者：
Caronia LM;Martin C;Welt CK;Sykiotis GP;Quinton R;Thambundit A;Avbelj M;Dhruvakumar S;Plummer L;Hughes VA;Seminara SB;Boepple PA;Sidis Y;Crowley WF Jr;Martin KA;Hall JE;Pitteloud N
功能性下丘脑闭经是促性腺激素释放激素(GnRH)缺乏的一种可逆性形式，通常由过度运动、营养不良或心理困扰等应激源引发。女性对这类应激源抑制生殖轴的敏感性各不相同，但尚不清楚这种差异是否反映了下丘脑闭经的遗传易感性。我们假设，与特发性低促性腺激素减退症相关的基因突变与下丘脑闭经有关。我们分析了55例下丘脑闭经妇女的特发性低促性腺激素低促性腺功能低下症相关基因的编码序列，并对已鉴定的突变进行了体外研究。在55例下丘脑闭经患者中有7例发现6个杂合性突变：成纤维细胞生长因子受体1基因FGFR1的2个变异(G260E和R756H)，原运动素受体2基因PROKR2的2个变异(R85H和L173R)，GnRH受体基因GNRHR(R262Q)的1个突变，以及Kall-Mann综合征1序列基因KAL1(V371I)的1个变异。在422名月经周期正常的对照组中没有发现突变。体外研究表明，FGFR1 G260E、FGFR1 R756H和PROKR2 R85H是功能缺失突变，正如之前对PROKR2 L173R和GNRHR R262Q所显示的那样。在下丘脑闭经的女性中，发现了与特发性低促性腺激素减退症相关的罕见基因变异，这表明这些突变可能导致女性对GnRH分泌功能变化的易感性，这种变化是下丘脑闭经的特征。我们的观察结果为罕见变异在常见多因素疾病中的作用提供了证据。(由尤尼斯·肯尼迪·施莱弗国家儿童健康和人类发展研究所等资助；ClinicalTrials.gov编号，NCT00494169。)
Functional hypothalamic amenorrhea is a reversible form of gonadotropin-releasing hormone (GnRH) deficiency commonly triggered by stressors such as excessive exercise, nutritional deficits, or psychological distress. Women vary in their susceptibility to inhibition of the reproductive axis by such stressors, but it is unknown whether this variability reflects a genetic predisposition to hypothalamic amenorrhea. We hypothesized that mutations in genes involved in idiopathic hypogonadotropic hypogonadism, a congenital form of GnRH deficiency, are associated with hypothalamic amenorrhea. We analyzed the coding sequence of genes associated with idiopathic hypogonadotropic hypogonadism in 55 women with hypothalamic amenorrhea and performed in vitro studies of the identified mutations. Six heterozygous mutations were identified in 7 of the 55 patients with hypothalamic amenorrhea: two variants in the fibroblast growth factor receptor 1 gene FGFR1 (G260E and R756H), two in the prokineticin receptor 2 gene PROKR2 (R85H and L173R), one in the GnRH receptor gene GNRHR (R262Q), and one in the Kall-mann syndrome 1 sequence gene KAL1 (V371I). No mutations were found in a cohort of 422 controls with normal menstrual cycles. In vitro studies showed that FGFR1 G260E, FGFR1 R756H, and PROKR2 R85H are loss-of-function mutations, as has been previously shown for PROKR2 L173R and GNRHR R262Q. Rare variants in genes associated with idiopathic hypogonadotropic hypogonadism are found in women with hypothalamic amenorrhea, suggesting that these mutations may contribute to the variable susceptibility of women to the functional changes in GnRH secretion that characterize hypothalamic amenorrhea. Our observations provide evidence for the role of rare variants in common multifactorial disease. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; ClinicalTrials.gov number, NCT00494169.)