Biallelic Mutations in Nuclear Pore Complex Subunit NUP107 Cause Early-Childhood-Onset Steroid-Resistant Nephrotic Syndrome

• DOI: 10.1016/j.ajhg.2015.08.013
• Publication Date: 2015-09-24T21:41:26Z
• Authors: Noriko Miyake; Hiroyasu Tsukaguchi; Eriko Koshimizu; Akemi Shono; Satoko Matsunaga; Masaaki Shiina; Yasuhiro Mimura; Shintaro Imamura; Tomonori Hirose; Koji Okudela; Kandai Nozu; Yuko Akioka; Motoshi Hattori; Norishige Yoshikawa; Akiko Kitamura; Hae Il Cheong; Shoji Kagami; Michiaki Yamashita; Atsushi Fujita; Satoko Miyatake; Yoshinori Tsurusaki; Mitsuko Nakashima; Hirotomo Saitsu; Kenichi Ohashi; Naoko Imamoto; Akihide Ryo; Kazuhiro Ogata; Kazumoto Iijima; Naomichi Matsumoto
• Keywords: Male; Cytoplasm; 0303 health sciences; Nephrotic Syndrome; Immunoblotting; Infant; Kidney; Nuclear Pore Complex Proteins; 03 medical and health sciences; Haplotypes; Microscopy, Fluorescence; Child, Preschool; Mutation; Genetics; Nuclear Pore; Animals; Humans; Immunoprecipitation; Genetics(clinical); Female; Age of Onset; Child; Alleles; Cells, Cultured

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.