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. Kemper, Martin Pohl, Fatih Ozaltin, Martin KonradRadovan Bogdanovic, Rainer Büscher, Udo Helmchen, Erkin Serdaroglu, Richard P. Lifton, Wolfram Antonin, Friedhelm Hildebrandt

Research output: Contribution to journalArticle

70 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)457-465
Number of pages9
JournalNature Genetics
Volume48
Issue number4
DOIs
Publication statusPublished - 2016 Mar 29

All Science Journal Classification (ASJC) codes

  • Genetics

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    Braun, D. A., Sadowski, C. E., Kohl, S., Lovric, S., Astrinidis, S. A., Pabst, W. L., Gee, H. Y., Ashraf, S., Lawson, J. A., Shril, S., Airik, M., Tan, W., Schapiro, D., Rao, J., Choi, W. I., Hermle, T., Kemper, M. J., Pohl, M., Ozaltin, F., ... Hildebrandt, F. (2016). Mutations in nuclear pore genes NUP93, NUP205 and XPO5 cause steroid-resistant nephrotic syndrome. Nature Genetics, 48(4), 457-465. https://doi.org/10.1038/ng.3512