Biallelic Mutations in Nuclear Pore Complex Subunit NUP107 Cause Early-Childhood-Onset Steroid-Resistant Nephrotic Syndrome
Biallelic Mutations in Nuclear Pore Complex Subunit NUP107 Cause Early-Childhood-Onset Steroid-Resistant Nephrotic Syndrome
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DOI：
10.1016/j.ajhg.2015.08.013
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发表时间：
2015-10-01
影响因子：
9.8
通讯作者：
Matsumoto, Naomichi
中科院分区：
文献类型：
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作者：
Miyake, Noriko;Tsukaguchi, Hiroyasu;Matsumoto, Naomichi
核孔复合体(NPC)是嵌入核膜中的一种巨大的蛋白质复合体。它在核质转运、核骨架和基因调控中起着中心作用。核孔蛋白107 kDa(NUP107)是鼻咽癌中央支架的组成部分，是所有真核细胞所必需的蛋白质。在这里，我们报告了来自五个无关家系的9名患者的双等位基因NUP107突变，这些患者表现为早发性激素抵抗型肾病综合征(SRN)。这些人患有病理性局灶性节段性肾小球硬化，这种疾病导致终末期肾脏疾病的频率很高。NUP107广泛表达，包括肾小球足细胞。在受影响的个体中检测到的四个NUP107突变中，有三个在体外阻碍了NUP107与NUP133(核孔蛋白133 kDa)的结合和NUP107与NPC的结合。由吗啉寡核苷酸产生的nup107基因敲除的斑马鱼表现出发育不良的肾小球结构和异常的足细胞足突，从而模拟了携带NUP107突变的SRNS个体肾脏的病理变化。考虑到足细胞的独特性质(高度分化的足突结构和裂隙膜以及不能再生)，我们提出了双等位基因NUP107突变导致的足细胞损伤模型作为SRNS的发病机制。
The nuclear pore complex (NPC) is a huge protein complex embedded in the nuclear envelope. It has central functions in nucleocytoplasmic transport, nuclear framework, and gene regulation. Nucleoporin 107 kDa (NUP107) is a component of the NPC central scaffold and is an essential protein in all eukaryotic cells. Here, we report on biallelic NUP107 mutations in nine affected individuals who are from five unrelated families and show early-onset steroid-resistant nephrotic syndrome (SRN). These individuals have pathologically focal segmental glomerulosclerosis, a condition that leads to end-stage renal disease with high frequency. NUP107 is ubiquitously expressed, including in glomerular podocytes. Three of four NUP107 mutations detected in the affected individuals hamper NUP107 binding to NUP133 (nucleoporin 133 kDa) and NUP107 incorporation into NPCs in vitro. Zebrafish with nup107 knockdown generated by morpholino oligonucleotides displayed hypoplastic glomerulus structures and abnormal podocyte foot processes, thereby mimicking the pathological changes seen in the kidneys of the SRNS individuals with NUP107 mutations. Considering the unique properties of the podocyte (highly differentiated foot-process architecture and slit membrane and the inability to regenerate), we propose a "podocyte-injury model" as the pathomechanism for SRNS due to biallelic NUP107 mutations.