Institute for Genomic Medicine, Rady Children's Hospital, University of California, San Diego, La Jolla, California, USA.
Nat Genet. 2012 Jun 24;44(8):941-5. doi: 10.1038/ng.2329.
De novo somatic mutations in focal areas are well documented in diseases such as neoplasia but are rarely reported in malformation of the developing brain. Hemimegalencephaly (HME) is characterized by overgrowth of either one of the two cerebral hemispheres. The molecular etiology of HME remains a mystery. The intractable epilepsy that is associated with HME can be relieved by the surgical treatment hemispherectomy, allowing sampling of diseased tissue. Exome sequencing and mass spectrometry analysis in paired brain-blood samples from individuals with HME (n = 20 cases) identified de novo somatic mutations in 30% of affected individuals in the PIK3CA, AKT3 and MTOR genes. A recurrent PIK3CA c.1633G>A mutation was found in four separate cases. Identified mutations were present in 8-40% of sequenced alleles in various brain regions and were associated with increased neuronal S6 protein phosphorylation in the brains of affected individuals, indicating aberrant activation of mammalian target of rapamycin (mTOR) signaling. Thus HME is probably a genetically mosaic disease caused by gain of function in phosphatidylinositol 3-kinase (PI3K)-AKT3-mTOR signaling.
在诸如肿瘤等疾病中，局灶性区域的新生体突变已有充分的文献记载，但在发育中大脑的畸形中很少有报道。偏侧巨脑症（HME）的特征是两个大脑半球中的一个过度生长。HME 的分子病因仍然是个谜。与 HME 相关的难治性癫痫可以通过手术治疗半球切除术来缓解，从而可以对病变组织进行采样。对来自 HME 患者（n=20 例）的配对脑-血样本进行外显子组测序和质谱分析，在 PIK3CA、AKT3 和 MTOR 基因中发现了 30%受影响个体的新生体体细胞突变。在四个单独的病例中发现了反复出现的 PIK3CA c.1633G>A 突变。在不同脑区的测序等位基因中，鉴定出的突变存在于 8%-40%之间，与受影响个体大脑中神经元 S6 蛋白磷酸化增加有关，表明哺乳动物雷帕霉素靶蛋白（mTOR）信号的异常激活。因此，HME 可能是一种由 PI3K-AKT3-mTOR 信号转导获得性功能异常引起的遗传镶嵌疾病。
