ESTROGEN RESISTANCE CAUSED BY A MUTATION IN THE ESTROGEN-RECEPTOR GENE IN A MAN
ESTROGEN RESISTANCE CAUSED BY A MUTATION IN THE ESTROGEN-RECEPTOR GENE IN A MAN
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DOI：
10.1056/nejm199410203311604
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发表时间：
1994-10-20
影响因子：
158.5
通讯作者：
KORACH, KS
中科院分区：
文献类型：
--
作者：
SMITH, EP;BOYD, J;KORACH, KS
背景和方法。雌激素受体基因的突变被认为是致命的。一名28岁的男性，其雌激素抵抗是由雌激素受体基因的破坏性突变引起的，接受了垂体性腺功能和骨密度的研究，并接受了6个月的经皮雌激素治疗。从淋巴细胞中提取雌激素受体DNA，通过单链构象多态性分析和直接测序进行评价。患者身高（204 cm [80.3 in.]）骨骺闭合不完全，尽管青春期发育正常，但成年后仍有持续线性生长的历史。他通常是男性化的，双侧腋窝黑棘皮病。血清雌二醇和雌酮浓度升高，血清睾酮浓度正常。血清促卵泡激素和促黄体激素浓度升高。葡萄糖耐量受损，存在高胰岛素血症。腰椎骨密度为0.745 g/cm 2，比年龄匹配的正常女性的平均值低3.1 SD;有骨转换增加的生化证据。尽管血清游离雌二醇浓度增加了10倍，但患者对雌激素给药没有可检测到的反应。其雌激素受体基因的构象分析显示外显子2的带型变异。外显子2的直接测序显示，在两个等位基因的密码子157胞嘧啶到胸腺嘧啶的转换，导致在一个过早的终止密码子。患者的父母是该突变的杂合子携带者，家系分析显示有血缘关系。人类雌激素受体的破坏不一定是致命的。雌激素对男性和女性的骨成熟和矿化都很重要。
Background and Methods. Mutations in the estrogen-receptor gene have been thought to be lethal. A 28-year-old man whose estrogen resistance was caused by a disruptive mutation in the estrogen-receptor gene underwent studies of pituitary-gonadal function and bone density and received transdermal estrogen for six months. Estrogen-receptor DNA, extracted from lymphocytes, was evaluated by analysis of single-strand-conformation polymorphisms and by direct sequencing.Results. The patient was tall (204 cm [80.3 in.]) and had incomplete epiphyseal closure, with a history of continued linear growth into adulthood despite otherwise normal pubertal development. He was normally masculinized and had bilateral axillary acanthosis nigricans. Serum estradiol and estrone concentrations were elevated, and serum testosterone concentrations were normal. Serum follicle-stimulating hormone and luteinizing hormone concentrations were increased. Glucose tolerance was impaired, and hyperinsulinemia was present. The bone mineral density of the lumbar spine was 0.745 g per square centimeter, 3.1 SD below the mean for age-matched normal women; there was biochemical evidence of increased bone turnover.The patient had no detectable response to estrogen administration, despite a 10-fold increase in the serum free estradiol concentration. Conformation analysis of his estrogen-receptor gene revealed a variant banding pattern in exon 2. Direct sequencing of exon 2 revealed a cytosine-to-thymine transition at codon 157 of both alleles, resulting in a premature stop codon. The patient's parents were heterozygous carriers of this mutation, and pedigree analysis revealed consanguinity.Conclusions. Disruption of the estrogen receptor in humans need not be lethal. Estrogen is important for bone maturation and mineralization in men as well as women.