Pathogenic Variants in NUP214 Cause "Plugged'' Nuclear Pore Channels and Acute Febrile Encephalopathy
Pathogenic Variants in NUP214 Cause "Plugged'' Nuclear Pore Channels and Acute Febrile Encephalopathy
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DOI：
10.1016/j.ajhg.2019.05.003
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发表时间：
2019-07-03
影响因子：
9.8
通讯作者：
Edvardson, Simon
中科院分区：
文献类型：
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作者：
Fichtman, Boris;Harel, Tamar;Edvardson, Simon
我们报告了编码人类核孔蛋白NUP214基因的双等位错义和移码致病变异导致急性发热性脑病。临床症状包括神经发育倒退、癫痫发作、肌阵挛、进行性小头畸形和小脑萎缩。患者来源的原代皮肤成纤维细胞中NUP214和NUP88蛋白水平降低，而核孔复合体的总数和密度保持正常。核转运分析显示，在受影响的细胞中，经典的蛋白质输入和信使核糖核酸输出通路存在缺陷。扫描电子显微镜对成纤维细胞核的直接表面成像显示，在受影响的细胞的核孔道中，中央颗粒(称为“塞子”)的存在大量增加。这一观察结果表明，大型运输货物可能会延迟通过核孔通道，影响其选择性屏障功能。将受影响个体的成纤维细胞暴露在热休克下，导致其应激反应明显延迟，随后细胞凋亡激增。这表明细胞培养中细胞存活率下降与受影响个体的严重发热诱导的脑损伤之间存在机械联系。我们的研究通过在单个核孔水平上直接成像来提供与人类疾病相关的功能变化的证据。
We report biallelic missense and frameshift pathogenic variants in the gene encoding human nucleoporin NUP214 causing acute febrile encephalopathy. Clinical symptoms include neurodevelopmental regression, seizures, myoclonic jerks, progressive microcephaly, and cerebellar atrophy. NUP214 and NUP88 protein levels were reduced in primary skin fibroblasts derived from affected individuals, while the total number and density of nuclear pore complexes remained normal. Nuclear transport assays exhibited defects in the classical protein import and mRNA export pathways in affected cells. Direct surface imaging of fibroblast nuclei by scanning electron microscopy revealed a large increase in the presence of central particles (known as "plugs'') in the nuclear pore channels of affected cells. This observation suggests that large transport cargoes may be delayed in passage through the nuclear pore channel, affecting its selective barrier function. Exposure of fibroblasts from affected individuals to heat shock resulted in a marked delay in their stress response, followed by a surge in apoptotic cell death. This suggests a mechanistic link between decreased cell survival in cell culture and severe fever-induced brain damage in affected individuals. Our study provides evidence by direct imaging at the single nuclear pore level of functional changes linked to a human disease.