title: Biallelic Mutations in Nuclear Pore Complex Subunit NUP107 Cause Early-Childhood-Onset Steroid-Resistant Nephrotic Syndrome.
abstract: 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.
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Miyake
authors.affiliation: Second Department of Internal Medicine, Kansai Medical University, Osaka 570-8507, Japan. Electronic address: tsukaguh@hirakata.kmu.ac.jp.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Tsukaguchi
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors.forename: Eriko
authors.initials: E
authors.lastname: Koshimizu
authors.affiliation: Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
authors.forename: Akemi
authors.initials: A
authors.lastname: Shono
authors.affiliation: Department of Microbiology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Matsunaga
authors.affiliation: Department of Biochemistry, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Shiina
authors.affiliation: Cellular Dynamics Laboratory, RIKEN, Wako 351-0198, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Mimura
authors.affiliation: National Research Institute of Fisheries Science, Yokohama 236-8648, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Imamura
authors.affiliation: Department of Molecular Biology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Hirose
authors.affiliation: Department of Pathology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Okudela
authors.affiliation: Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
authors.forename: Kandai
authors.initials: K
authors.lastname: Nozu
authors.affiliation: Department of Pediatric Nephrology, Tokyo Women's Medical University, Tokyo 162-8666, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Akioka
authors.affiliation: Department of Pediatric Nephrology, Tokyo Women's Medical University, Tokyo 162-8666, Japan.
authors.forename: Motoshi
authors.initials: M
authors.lastname: Hattori
authors.affiliation: Center for Clinical Research and Development, National Center for Child Health and Development, Tokyo 157-8535, Japan.
authors.forename: Norishige
authors.initials: N
authors.lastname: Yoshikawa
authors.affiliation: Department of Immunology & Parasitology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Kitamura
authors.affiliation: Department of Pediatrics, Seoul National University Children's Hospital, Seoul 03080, Korea; Research Coordination Center for Rare Diseases, Seoul National University Hospital, Seoul 03080, Korea; Kidney Research Institute, Medical Research Center, Seoul National University College of Medicine, Seoul 03080, Korea.
authors.forename: Hae Il
authors.initials: HI
authors.lastname: Cheong
authors.affiliation: Department of Pediatrics, University of Tokushima Graduate School, Tokushima 770-8503, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Kagami
authors.affiliation: National Research Institute of Fisheries Science, Yokohama 236-8648, Japan.
authors.forename: Michiaki
authors.initials: M
authors.lastname: Yamashita
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Fujita
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Miyatake
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Tsurusaki
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Nakashima
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors.forename: Hirotomo
authors.initials: H
authors.lastname: Saitsu
authors.affiliation: Department of Pathology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Ohashi
authors.affiliation: Cellular Dynamics Laboratory, RIKEN, Wako 351-0198, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Imamoto
authors.affiliation: Department of Microbiology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors.forename: Akihide
authors.initials: A
authors.lastname: Ryo
authors.affiliation: Department of Biochemistry, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ogata
authors.affiliation: Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
authors.forename: Kazumoto
authors.initials: K
authors.lastname: Iijima
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan. Electronic address: naomat@yokohama-cu.ac.jp.
authors.forename: Naomichi
authors.initials: N
authors.lastname: Matsumoto
mesh_terms: D017668:Age of Onset; D000483:Alleles; D000818:Animals; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D006239:Haplotypes; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D007223:Infant; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008297:Male; D008856:Microscopy, Fluorescence; D009154:Mutation / Q000235:genetics*; D009404:Nephrotic Syndrome / Q000151:congenital* / Q000209:etiology / Q000473:pathology; D022022:Nuclear Pore; D028861:Nuclear Pore Complex Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D020320:Oligoribonucleotides, Antisense / Q000494:pharmacology; D010375:Pedigree; D050199:Podocytes / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015027:Zebrafish / Q000235:genetics* / Q000254:growth & development; D029961:Zebrafish Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: C512772:NUP107 protein, human; C577582:NUP107 protein, zebrafish; D028861:Nuclear Pore Complex Proteins; D020320:Oligoribonucleotides, Antisense; D012333:RNA, Messenger; D029961:Zebrafish Proteins