Estrogen excess associated with novel gain-of-function mutations affecting the aromatase gene
Estrogen excess associated with novel gain-of-function mutations affecting the aromatase gene
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DOI：
10.1056/nejmoa021559
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发表时间：
2003-05-08
影响因子：
158.5
通讯作者：
Bulun, SE
中科院分区：
文献类型：
--
作者：
Shozu, M;Sebastian, S;Bulun, SE
背景：青春期前发病的男性乳房发育症可能是由于腺外组织中芳香酶活性过高而导致雌激素增加所致。染色体 15q21.2 中的一个基因编码芳香酶，这是雌激素生物合成的关键酶。几种生理组织特异性启动子调节芳香酶的表达，产生具有相同编码区但在胎盘、性腺、大脑、脂肪和皮肤中具有组织特异性 5'-非翻译区的信使 RNA (mRNA) 物种。 方法：我们研究了一名 36 岁男子、他 7 岁儿子和一名患有严重男性乳房发育症的无关 17 岁男孩的皮肤、脂肪和血液样本。青春期前发病和雌激素水平升高引起的低促性腺激素性性腺功能减退症。结果：脂肪和皮肤中的芳香酶活性和mRNA水平以及雄烯二酮的全身芳香化严重升高。使用芳香酶抑制剂治疗可降低血清雌激素水平，并使促性腺激素和睾酮水平恢复正常。芳香酶 mRNA 的 5'-非翻译区在父亲和儿子中包含相同的序列（FLJ），在不相关的男孩中包含另一个序列（TMOD3）；在对照受试者中没有发现这两种序列。这些 5'-非翻译区通常构成按以下顺序（从端粒到着丝粒）聚集在染色体 15q21.2-3 中的两个普遍表达基因的第一个外显子：FLJ、TMOD3 和芳香酶。芳香酶基因通常以与TMOD3和FLJ相反的方向转录。两个不同的杂合倒位逆转了患者中 TMOD3 或 FLJ 启动子的方向。结论：染色体 15q21.2-3 中的杂合倒位导致芳香酶基因的编码区与通常转录其他基因的组成型活性隐性启动子相邻，由于芳香酶在许多组织中过度表达，导致严重的雌激素过量。
BACKGROUND:Gynecomastia of prepubertal onset may result from increased estrogen owing to excessive aromatase activity in extraglandular tissues. A gene in chromosome 15q21.2 encodes aromatase, the key enzyme for estrogen biosynthesis. Several physiologic tissue-specific promoters regulate the expression of aromatase, giving rise to messenger RNA (mRNA) species with an identical coding region but tissue-specific 5'-untranslated regions in placenta, gonads, brain, fat, and skin.METHODS:We studied skin, fat, and blood samples from a 36-year-old man, his 7-year-old son, and an unrelated 17-year-old boy with severe gynecomastia of prepubertal onset and hypogonadotropic hypogonadism caused by elevated estrogen levels.RESULTS:Aromatase activity and mRNA levels in fat and skin and whole-body aromatization of androstenedione were severely elevated. Treatment with an aromatase inhibitor decreased serum estrogen levels and normalized gonadotropin and testosterone levels. The 5'-untranslated regions of aromatase mRNA contained the same sequence (FLJ) in the father and son and another sequence (TMOD3) in the unrelated boy; neither sequence was found in control subjects. These 5'-untranslated regions normally make up the first exons of two ubiquitously expressed genes clustered in chromosome 15q21.2-3 in the following order (from telomere to centromere): FLJ, TMOD3, and aromatase. The aromatase gene is normally transcribed in the direction opposite to that of TMOD3 and FLJ. Two distinct heterozygous inversions reversed the direction of the TMOD3 or FLJ promoter in the patients.CONCLUSIONS:Heterozygous inversions in chromosome 15q21.2-3, which caused the coding region of the aromatase gene to lie adjacent to constitutively active cryptic promoters that normally transcribe other genes, resulted in severe estrogen excess owing to the overexpression of aromatase in many tissues.