Miyake Noriko, Tsukaguchi Hiroyasu, Koshimizu Eriko, Shono Akemi, Matsunaga Satoko, Shiina Masaaki, Mimura Yasuhiro, Imamura Shintaro, Hirose Tomonori, Okudela Koji, Nozu Kandai, Akioka Yuko, Hattori Motoshi, Yoshikawa Norishige, Kitamura Akiko, Cheong Hae Il, Kagami Shoji, Yamashita Michiaki, Fujita Atsushi, Miyatake Satoko, Tsurusaki Yoshinori, Nakashima Mitsuko, Saitsu Hirotomo, Ohashi Kenichi, Imamoto Naoko, Ryo Akihide, Ogata Kazuhiro, Iijima Kazumoto, Matsumoto Naomichi
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
Second Department of Internal Medicine, Kansai Medical University, Osaka 570-8507, Japan.
Am J Hum Genet. 2015 Oct 1;97(4):555-66. doi: 10.1016/j.ajhg.2015.08.013. Epub 2015 Sep 24.
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 (SRNS). 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.
核孔复合体（NPC）是一种嵌入核膜的巨大蛋白质复合体。它在核质运输、核骨架和基因调控中发挥着核心作用。核孔蛋白107 kDa（NUP107）是NPC中央支架的一个组成部分，是所有真核细胞中的一种必需蛋白质。在此，我们报告了来自五个无关家庭的九名受影响个体中的双等位基因NUP107突变，这些个体表现为早发性类固醇抵抗性肾病综合征（SRNS）。这些个体在病理上表现为局灶节段性肾小球硬化，这种病症会高频导致终末期肾病。NUP107在包括肾小球足细胞在内的所有细胞中普遍表达。在受影响个体中检测到的四个NUP107突变中有三个在体外会妨碍NUP107与NUP133（核孔蛋白133 kDa）结合以及NUP107并入NPC。通过吗啉代寡核苷酸敲低nup107的斑马鱼表现出肾小球结构发育不全和足细胞足突异常，从而模拟了具有NUP107突变的SRNS个体肾脏中所见的病理变化。考虑到足细胞的独特特性（高度分化的足突结构和裂孔隔膜以及无法再生），我们提出“足细胞损伤模型”作为双等位基因NUP107突变导致SRNS的发病机制。
