Sex hormones in autism: androgens and estrogens differentially and reciprocally regulate RORA, a novel candidate gene for autism.
Sex hormones in autism: androgens and estrogens differentially and reciprocally regulate RORA, a novel candidate gene for autism.
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DOI：
10.1371/journal.pone.0017116
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发表时间：
2011-02-16
期刊：
影响因子：
3.7
通讯作者：
Hu VW
中科院分区：
文献类型：
--
作者：
Sarachana T;Xu M;Wu RC;Hu VW
孤独症是一种广泛的神经发育障碍，表现为社会行为和人际交往的缺陷，以及刻板的重复行为，令人费解的是，男性的比例为1.44 ∶1，对于性激素是否或如何在孤独症易感性中发挥作用没有明确的理解。在这里，我们表明，男性和女性激素差异调节一种新的自闭症候选基因，视黄酸相关孤儿受体-α（RORA）在神经元细胞系，SH-SY 5 Y的表达。此外，我们证明RORA转录调节芳香酶，一种将睾酮转化为雌激素的酶。我们进一步表明，芳香化酶蛋白显着减少，在额叶皮层的自闭症患者相对于性别和年龄匹配的控制，并与RORA蛋白水平在大脑中。这些结果表明，RORA有可能通过其转录靶点之一芳香酶分别受到雄性激素和雌性激素的负反馈和正反馈调节，并进一步表明了自闭症中引入性别偏见的机制。
Autism, a pervasive neurodevelopmental disorder manifested by deficits in social behavior and interpersonal communication, and by stereotyped, repetitive behaviors, is inexplicably biased towards males by a ratio of ∼4∶1, with no clear understanding of whether or how the sex hormones may play a role in autism susceptibility. Here, we show that male and female hormones differentially regulate the expression of a novel autism candidate gene, retinoic acid-related orphan receptor-alpha (RORA) in a neuronal cell line, SH-SY5Y. In addition, we demonstrate that RORA transcriptionally regulates aromatase, an enzyme that converts testosterone to estrogen. We further show that aromatase protein is significantly reduced in the frontal cortex of autistic subjects relative to sex- and age-matched controls, and is strongly correlated with RORA protein levels in the brain. These results indicate that RORA has the potential to be under both negative and positive feedback regulation by male and female hormones, respectively, through one of its transcriptional targets, aromatase, and further suggest a mechanism for introducing sex bias in autism.
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