Almuriekhi Mariam, Shintani Takafumi, Fahiminiya Somayyeh, Fujikawa Akihiro, Kuboyama Kazuya, Takeuchi Yasushi, Nawaz Zafar, Nadaf Javad, Kamel Hussein, Kitam Abu Khadija, Samiha Zaineddin, Mahmoud Laila, Ben-Omran Tawfeg, Majewski Jacek, Noda Masaharu
Section of Clinical and Metabolic Genetics, Department of Pediatrics, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar.
Division of Molecular Neurobiology, National Institute for Basic Biology, Okazaki 444-8787, Japan; School of Life Science, The Graduate University for Advanced Studies (SOKENDAI), Okazaki 444-8787, Japan.
Cell Rep. 2015 Mar 10;10(9):1585-1598. doi: 10.1016/j.celrep.2015.02.011. Epub 2015 Mar 5.
Sotos syndrome, characterized by intellectual disability and characteristic facial features, is caused by haploinsufficiency in the NSD1 gene. We conducted an etiological study on two siblings with Sotos features without mutations in NSD1 and detected a homozygous frameshift mutation in the APC2 gene by whole-exome sequencing, which resulted in the loss of function of cytoskeletal regulation in neurons. Apc2-deficient (Apc2) mice exhibited impaired learning and memory abilities along with an abnormal head shape. Endogenous Apc2 expression was downregulated by the knockdown of Nsd1, indicating that APC2 is a downstream effector of NSD1 in neurons. Nsd1 knockdown in embryonic mouse brains impaired the migration and laminar positioning of cortical neurons, as observed in Apc2 mice, and this defect was rescued by the forced expression of Apc2. Thus, APC2 is a crucial target of NSD1, which provides an explanation for the intellectual disability associated with Sotos syndrome.
索托斯综合征以智力残疾和特征性面部特征为特征，由NSD1基因单倍剂量不足引起。我们对两名具有索托斯特征但NSD1无突变的同胞进行了病因学研究，并通过全外显子组测序在APC2基因中检测到一个纯合移码突变，该突变导致神经元细胞骨架调节功能丧失。Apc2基因缺陷（Apc2）小鼠表现出学习和记忆能力受损以及头部形状异常。Nsd1基因敲低导致内源性Apc2表达下调，表明APC2是神经元中NSD1的下游效应因子。如在Apc2小鼠中观察到的那样，胚胎小鼠大脑中Nsd1基因敲低会损害皮质神经元的迁移和层状定位，而这种缺陷可通过强制表达Apc2得到挽救。因此，APC2是NSD1的关键靶点，这为与索托斯综合征相关的智力残疾提供了解释。
