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Mutations in nuclear pore genes NUP93, NUP205 and XPO5 cause steroid-resistant nephrotic syndrome.

 Daniela A. Braun  ;  Carolin E. Sadowski  ;  Stefan Kohl  ;  Svjetlana Lovric  ;  Susanne A. Astrinidis  ;  Werner L. Pabst  ;  Heon Yung Gee  ;  Shazia Ashraf  ;  Jennifer A. Lawson  ;  Shirlee Shril  ;  Merlin Airik  ;  Weizhen Tan  ;  David Schapiro  ;  Jia Rao  ;  Won-Il Choi  ;  Tobias Hermle  ;  Markus J. Kemper3, Martin Pohl4, Fatih Ozaltin5,6,7, Martin Konrad8, Radovan Bogdanovic9, Rainer Büscher10, Udo Helmchen  ;  Erkin Serdaroglu  ;  Richard P. Lifton  ;  Wolfram Antonin  ;  Friedhelm Hildebrandt 
 NATURE GENETICS, Vol.48(4) : 457-465, 2016 
Journal Title
Issue Date
Age of Onset ; Amino Acid Sequence ; Animals ; Cell Movement ; Cell Proliferation ; Cells, Cultured ; Child ; Child, Preschool ; Drug Resistance/genetics ; Female ; Genes, Recessive ; Genetic Association Studies ; Genetic Linkage ; HEK293 Cells ; Humans ; Infant ; Karyopherins/genetics* ; Karyopherins/metabolism ; Male ; Mice ; Molecular Sequence Data ; Mutation ; Nephrotic Syndrome/drug therapy ; Nephrotic Syndrome/genetics* ; Nuclear Pore Complex Proteins/genetics* ; Nuclear Pore Complex Proteins/metabolism ; Oxidative Stress ; Podocytes/physiology ; Sequence Analysis, DNA ; Steroids/pharmacology ; Steroids/therapeutic use ; Xenopus laevis
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.
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1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
Gee, Heon Yung(지헌영) ORCID logo https://orcid.org/0000-0002-8741-6177
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