Kelberman Daniel, Rizzoti Karine, Avilion Ariel, Bitner-Glindzicz Maria, Cianfarani Stefano, Collins Julie, Chong W Kling, Kirk Jeremy M W, Achermann John C, Ross Richard, Carmignac Danielle, Lovell-Badge Robin, Robinson Iain C A F, Dattani Mehul T
London Centre for Paediatric Endocrinology, Biochemistry, Endocrinology, Institute of Child Health, University College London, London, United Kingdom.
J Clin Invest. 2006 Sep;116(9):2442-55. doi: 10.1172/JCI28658. Epub 2006 Aug 24.
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 anophthalmia/microphthalmia, 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.
转录因子SOX2最显著地表达于发育中的中枢神经系统和基板，在胚胎发生中发挥关键作用。此前，SOX2的杂合新发突变与双侧无眼/小眼、发育迟缓、身材矮小和男性生殖道异常有关。在此，我们研究了Sox2在小鼠垂体发育中的作用。Sox2靶向破坏的杂合小鼠未表现出眼部缺陷，但显示出垂体前叶发育异常，生长激素、促黄体生成素和促甲状腺激素水平降低。因此，我们在235名患者队列中鉴定出8名SOX2存在杂合序列变异的个体。其中6个是新发突变，预计会导致截短的蛋白质产物，表现出部分或完全功能丧失（DNA结合、核转位或反式激活）。临床评估显示，除双侧眼部缺陷外，SOX2突变还与垂体前叶发育不全和低促性腺激素性性腺功能减退、影响胼胝体和内侧颞叶结构的可变缺陷、下丘脑错构瘤、感音神经性听力损失和食管闭锁有关。我们的数据表明，SOX2对人类和小鼠下丘脑-垂体轴及生殖轴的正常发育和功能是必需 的。
