title: Mutations in nuclear pore genes NUP93, NUP205 and XPO5 cause steroid-resistant nephrotic syndrome.
abstract: Nucleoporins are essential components of the nuclear pore complex (NPC). Only a few diseases have been attributed to NPC dysfunction. Steroid-resistant nephrotic syndrome (SRNS), a frequent cause of chronic kidney disease, is caused by dysfunction of glomerular podocytes. Here we identify in eight families with SRNS mutations in NUP93, its interaction partner NUP205 or XPO5 (encoding exportin 5) as hitherto unrecognized monogenic causes of SRNS. NUP93 mutations caused disrupted NPC assembly. NUP93 knockdown reduced the presence of NUP205 in the NPC, and, reciprocally, a NUP205 alteration abrogated NUP93 interaction. We demonstrate that NUP93 and exportin 5 interact with the signaling protein SMAD4 and that NUP93 mutations abrogated interaction with SMAD4. Notably, NUP93 mutations interfered with BMP7-induced SMAD transcriptional reporter activity. We hereby demonstrate that mutations of NUP genes cause a distinct renal disease and identify aberrant SMAD signaling as a new disease mechanism of SRNS, opening a potential new avenue for treatment.
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Daniela A
authors.initials: DA
authors.lastname: Braun
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Carolin E
authors.initials: CE
authors.lastname: Sadowski
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kohl
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Svjetlana
authors.initials: S
authors.lastname: Lovric
authors.affiliation: Friedrich Miescher Laboratory, Max Planck Society, Tübingen, Germany.
authors.forename: Susanne A
authors.initials: SA
authors.lastname: Astrinidis
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Werner L
authors.initials: WL
authors.lastname: Pabst
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Heon Yung
authors.initials: HY
authors.lastname: Gee
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Shazia
authors.initials: S
authors.lastname: Ashraf
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Lawson
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Shirlee
authors.initials: S
authors.lastname: Shril
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Merlin
authors.initials: M
authors.lastname: Airik
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Weizhen
authors.initials: W
authors.lastname: Tan
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: David
authors.initials: D
authors.lastname: Schapiro
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Rao
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Won-Il
authors.identifier: http://orcid.org/0000-0002-4837-0436
authors.initials: WI
authors.lastname: Choi
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Tobias
authors.initials: T
authors.lastname: Hermle
authors.affiliation: Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Kemper
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University of Freiburg Medical Center, Freiburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Pohl
authors.affiliation: Department of Pediatric Nephrology, Hacettepe University Faculty of Medicine, Ankara, Turkey.|Nephrogenetics Laboratory, Hacettepe University, Ankara, Turkey.|Center for Biobanking and Genomics, Hacettepe University, Ankara, Turkey.
authors.forename: Fatih
authors.initials: F
authors.lastname: Ozaltin
authors.affiliation: Department of General Pediatrics, University Hospital Münster, Münster, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Konrad
authors.affiliation: Medical Faculty, University of Belgrade, Belgrade, Serbia.
authors.forename: Radovan
authors.initials: R
authors.lastname: Bogdanovic
authors.affiliation: Department of Pediatrics II, Pediatric Nephrology, University of Duisburg-Essen, Essen, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Büscher
authors.affiliation: Institute of Pathology, Kidney Registry, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Udo
authors.initials: U
authors.lastname: Helmchen
authors.affiliation: Department of Pediatric Nephrology, Dr. Behçet Uz Children Hospital, Izmir, Turkey.
authors.forename: Erkin
authors.initials: E
authors.lastname: Serdaroglu
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.|Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
authors.affiliation: Friedrich Miescher Laboratory, Max Planck Society, Tübingen, Germany.
authors.forename: Wolfram
authors.initials: W
authors.lastname: Antonin
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
mesh_terms: D017668:Age of Onset; D000595:Amino Acid Sequence; D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D005808:Genes, Recessive; D056726:Genetic Association Studies; D008040:Genetic Linkage; D057809:HEK293 Cells; D006801:Humans; D007223:Infant; D028884:Karyopherins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009404:Nephrotic Syndrome / Q000188:drug therapy / Q000235:genetics*; D028861:Nuclear Pore Complex Proteins / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress; D050199:Podocytes / Q000502:physiology; D017422:Sequence Analysis, DNA; D013256:Steroids / Q000494:pharmacology / Q000627:therapeutic use; D014982:Xenopus laevis
chemical_list: D028884:Karyopherins; D028861:Nuclear Pore Complex Proteins; C000609717:Nup205 protein, human; C508154:Nup93 protein, human; D013256:Steroids; C446511:XPO5 protein, human