Mutations in multiple components of the nuclear pore complex cause nephrotic syndrome

Daniela A. Braun, Svjetlana Lovric, David Schapiro, Ronen Schneider, Jonathan Marquez, Maria Asif, Muhammad Sajid Hussain, Ankana Daga, Eugen Widmeier, Jia Rao, Shazia Ashraf, Weizhen Tan, C. Patrick Lusk, Amy Kolb, Tilman Jobst-Schwan, Johanna Magdalena Schmidt, Charlotte A. Hoogstraten, Kaitlyn Eddy, Thomas M. Kitzler, Shirlee ShrilAbubakar Moawia, Kathrin Schrage, Arwa Ishaq A. Khayyat, Jennifer A. Lawson, Heon Yung Gee, Jillian K. Warejko, Tobias Hermle, Amar J. Majmundar, Hannah Hugo, Birgit Budde, Susanne Motameny, Janine Altmüller, Angelika Anna Noegel, Hanan M. Fathy, Daniel P. Gale, Syeda Seema Waseem, Ayaz Khan, Larissa Kerecuk, Seema Hashmi, Nilufar Mohebbi, Robert Ettenger, Erkin Serdaroğlu, Khalid A. Alhasan, Mais Hashem, Sara Goncalves, Gema Ariceta, Mercedes Ubetagoyena, Wolfram Antonin, Shahid Mahmood Baig, Fowzan S. Alkuraya, Qian Shen, Hong Xu, Corinne Antignac, Richard P. Lifton, Shrikant Mane, Peter Nürnberg, Mustafa K. Khokha, Friedhelm Hildebrandt

Research output: Contribution to journalArticlepeer-review

41 Citations (Scopus)

Abstract

Steroid-resistant nephrotic syndrome (SRNS) almost invariably progresses to end-stage renal disease. Although more than 50 monogenic causes of SRNS have been described, a large proportion of SRNS remains unexplained. Recently, it was discovered that mutations of NUP93 and NUP205, encoding 2 proteins of the inner ring subunit of the nuclear pore complex (NPC), cause SRNS. Here, we describe mutations in genes encoding 4 components of the outer rings of the NPC, namely NUP107, NUP85, NUP133, and NUP160, in 13 families with SRNS. Using coimmunoprecipitation experiments, we showed that certain pathogenic alleles weakened the interaction between neighboring NPC subunits. We demonstrated that morpholino knockdown of nup107, nup85, or nup133 in Xenopus disrupted glomerulogenesis. Re-expression of WT mRNA, but not of mRNA reflecting mutations from SRNS patients, mitigated this phenotype. We furthermore found that CRISPR/Cas9 knockout of NUP107, NUP85, or NUP133 in podocytes activated Cdc42, an important effector of SRNS pathogenesis. CRISPR/ Cas9 knockout of nup107 or nup85 in zebrafish caused developmental anomalies and early lethality. In contrast, an in-frame mutation of nup107 did not affect survival, thus mimicking the allelic effects seen in humans. In conclusion, we discovered here that mutations in 4 genes encoding components of the outer ring subunits of the NPC cause SRNS and thereby provide further evidence that specific hypomorphic mutations in these essential genes cause a distinct, organ-specific phenotype.

Original languageEnglish
Pages (from-to)4313-4328
Number of pages16
JournalJournal of Clinical Investigation
Volume128
Issue number10
DOIs
Publication statusPublished - 2018 Oct 1

Bibliographical note

Funding Information:
This research was supported by grants from the NIH to FH (DK076683) and to MKK and CPL (HL124402). JM was supported by the Yale Medical Scientist Training Program (MSTP) (NIH grant T32 GM07205) and NIH grant T32 GM007223 from the Yale Predoctoral Program in Cellular and Molecular Biology. PN and AAN acknowledge support from the Center for Molecular Medicine Cologne. MSH was supported by the Köln Fortune Program of the Faculty of Medicine, University of Cologne. TJS was supported by grant Jo 1324/1-1 from the Deutsche Forsc-hungsgemeinschaft (DFG). EW was supported by the German National Academy of Sciences Leopoldina (LPDS-2015-07). AJM was supported by the Harvard Stem Cell Institute, Kidney Group. WT was supported by the ASN (American Society of Nephrology) Foundation for Kidney Research. TH was supported by the German Research Foundation, DFG fellowship (HE 7456/1-1). CA was supported by grants from the European Union’s Seventh Frame-work Programme (FP7/2007-2013/no 305608, EURenOmics), the Fondation Recherche Medicale (DEQ20150331682), and the Investments for the Future program (ANR-10-IAHU-01). SG was supported by the MD-PhD program of Imagine Institute (ANR-10-IAHU-01 and Fondation Bettencourt-Schueller). TMK was supported by a Post-Doctoral Fellowship award from the KRES-CENT Program, a national kidney research training partnership of the Kidney Foundation of Canada, the Canadian Society of Nephrology, and the Canadian Institutes of Health Research. MA, AM, and SSW were supported by the Higher Education Commission of Pakistan. AIAK is supported by King Saud University.

Funding Information:
This research was supported by grants from the NIH to FH (DK076683) and to MKK and CPL (HL124402). JM was supported by the Yale Medical Scientist Training Program (MSTP) (NIH grant T32 GM07205) and NIH grant T32 GM007223 from the Yale Predoctoral Program in Cellular and Molecular Biology. PN and AAN acknowledge support from the Center for Molecular Medicine Cologne. MSH was supported by the Köln Fortune Program of the Faculty of Medicine, University of Cologne. TJS was supported by grant Jo 1324/1-1 from the Deutsche Forsc-hungsgemeinschaft (DFG). EW was supported by the German National Academy of Sciences Leopoldina (LPDS-2015-07). AJM was supported by the Harvard Stem Cell Institute, Kidney Group. WT was supported by the ASN (American Society of Nephrology) Foundation for Kidney Research. TH was supported by the German Research Foundation, DFG fellowship (HE 7456/1-1). CA was supported by grants from the European Union's Seventh Framework Programme (FP7/2007-2013/no 305608, EURenOmics), the Fondation Recherche Medicale (DEQ20150331682), and the Investments for the Future program (ANR-10-IAHU-01). SG was supported by the MD-PhD program of Imagine Institute (ANR-10-IAHU-01 and Fondation Bettencourt-Schueller). TMK was supported by a Post-Doctoral Fellowship award from the KRES-CENT Program, a national kidney research training partnership of the Kidney Foundation of Canada, the Canadian Society of Nephrology, and the Canadian Institutes of Health Research. MA, AM, and SSW were supported by the Higher Education Commission of Pakistan. AIAK is supported by King Saud University.

Publisher Copyright:
© 2018 American Society for Clinical Investigation. All rights reserved.

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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