Wang Chao, Lin Longlong, Xue Yan, Wang Yilin, Liu Zhao, Ou Zicheng, Wu Shengnan, Lan Xiaoping, Zhang Yuanfeng, Yuan Fang, Luo Xiaona, Wang Chunmei, Xi Jiaming, Sun Xiaomin, Chen Yucai
Department of Neurology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China.
Institute of Medical Science, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Front Genet. 2020 Feb 27;11:129. doi: 10.3389/fgene.2020.00129. eCollection 2020.
The RNA polymerase II transcription subunit 12 homolog () is a member of the mediator complex, which plays a critical role in RNA transcription. Mutations in cause X-linked intellectual disability and other anomalies collectively grouped as -related disorders. While mutations have been most commonly reported in male patients, we present the case of a 1-year-old girl with clinical characteristics similar to related disorders. To explore the clinical characteristics of the condition and its possible pathogenesis, we analyzed the patient's clinical data; genetic testing by whole-exome sequencing revealed a heterozygous mutation (c.1249-1G > C) in . Further cDNA experiments revealed that the patient had an abnormal splicing at the skipping of exon9, which may have produced a truncated protein. qPCR showed decreased gene expression level in the patient, and an X-chromosome inactivation test confirmed a skewed inactivation of the X-chromosome. The lymphoblast transcription levels of the genes involved in the Gli3-dependent sonic hedgehog (SHH) signaling pathway, namely, , and , were found to be significantly elevated compared with those of her parents and sex- and age-matched controls. Our results support the view that mutations may dysregulate the SHH signaling pathway, which may have accounted for the aberrant craniofacial morphology of our patient.
RNA聚合酶II转录亚基12同源物（）是中介体复合物的成员，该复合物在RNA转录中起关键作用。中的突变会导致X连锁智力障碍和其他异常，这些异常统称为相关疾病。虽然突变在男性患者中报道最为常见，但我们报告了一例1岁女孩，其临床特征与相关疾病相似。为了探讨该病的临床特征及其可能的发病机制，我们分析了患者的临床资料；通过全外显子组测序进行的基因检测发现中的一个杂合突变（c.1249-1G > C）。进一步的cDNA实验表明，患者在第9外显子跳跃处存在异常剪接，这可能产生了截短的蛋白质。qPCR显示患者中基因表达水平降低，X染色体失活检测证实X染色体失活偏斜。与她的父母以及性别和年龄匹配的对照相比，发现参与Gli3依赖性音猬因子（SHH）信号通路的基因、和的淋巴母细胞转录水平显著升高。我们的结果支持这样一种观点，即突变可能会失调SHH信号通路，这可能解释了我们患者异常的颅面形态。
