Mutations within Sox2/SOX2 are associated with abnormalities in the hypothalamopituitary-gonadal axis in mice and humans
Mutations within Sox2/SOX2 are associated with abnormalities in the hypothalamopituitary-gonadal axis in mice and humans
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DOI：
10.1172/jci28658
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发表时间：
2006-09-01
影响因子：
15.9
通讯作者：
Dattani, Mehul T.
中科院分区：
文献类型：
--
作者：
Kelberman, Daniel;Rizzoti, Karine;Dattani, Mehul T.
转录因子SOX2在发育中的中枢神经系统和胎盘中表达最显著，在胚胎发生中起关键作用。SOX2基因的杂合子新生突变以前曾与双侧无咽/小咽畸形、发育迟缓、身材矮小和男性生殖道异常相关。在这里，我们研究了Sox2在小鼠脑垂体发育中的作用。SOX2基因杂合子突变的小鼠没有表现出眼睛缺陷，但显示出垂体前叶发育异常，生长激素、黄体生成素和促甲状腺激素水平降低。因此，我们从235名患者中确定了8名SOX2杂合序列变异的个体。其中6个是从头突变，预计会导致截短的蛋白质产物，表现出部分或完全的功能丧失(DNA结合、核转位或反式激活)。临床评估显示，除双眼缺陷外，SOX2基因突变还与垂体前叶发育不良和性腺激素减退、影响胼胝体和内侧颞叶结构的各种缺陷、下丘脑错构瘤、感音神经性听力损失和食道闭锁有关。我们的数据表明，SOX2对于人类和小鼠的下丘脑-垂体和生殖轴的正常发育和功能是必需的。
The transcription factor SOX2 is expressed most notably in the developing CNS and placodes, where it plays critical roles in embryogenesis. Heterozygous de novo mutations in SOX2 have previously been associated with bilateral anophthahnia/microphthahnia, developmental delay, short stature, and male genital tract abnormalities. Here we investigated the role of Sox2 in murine pituitary development. Mice heterozygous for a targeted disruption of Sox2 did not manifest eye defects, but showed abnormal anterior pituitary development with reduced levels of growth hormone, luteinizing hormone, and thyroid-stimulating hormone. Consequently, we identified 8 individuals (from a cohort of 235 patients) with heterozygous sequence variations in SOX2. Six of these were de novo mutations, predicted to result in truncated protein products, that exhibited partial or complete loss of function (DNA binding, nuclear translocation, or transactivation). Clinical evaluation revealed that, in addition to bilateral eye defects, SOX2 mutations were associated with anterior pituitary hypoplasia and hypogonadotropic hypogonadism,variable defects affecting the corpus callosum and mesial temporal structures, hypothalamic hamartoma, sensorineural hearing loss, and esophageal atresia. Our data show that SOX2 is necessary for the normal development and function of the hypothalamo-pituitary and reproductive axes in both humans and mice.