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

Braun DA, Lovric S, Schapiro D, Schneider R, Marquez J, Asif M, Hussain MS, Daga A, Widmeier E, Rao J, Ashraf S, Tan W, Lusk CP, Kolb A, Jobst-Schwan T, Schmidt JM, Hoogstraten CA, Eddy K, Kitzler TM, Shril S, Moawia A, Schrage K, Khayyat AIA, Lawson JA, Gee HY, Warejko JK, Hermle T, Majmundar AJ, Hugo H, Budde B, Motameny S, Altmueller J, Noegel AA, Fathy HM, Gale DP, Waseem SS, Khan A, Kerecuk L, Hashmi S, Mohebbi N, Ettenger R, Serdaroglu E, Alhasan KA, Hashem M, Goncalves S, Ariceta G, Ubetagoyena M, Antonin W, Baig SM, Alkuraya FS, Shen Q, Xu H, Antignac C, Lifton RP, Mane S, Nuernberg P, Khokha MK, Hildebrandt F (2018)

Publication Type: Journal article

Publication year: 2018

Journal

Book Volume: 128

Pages Range: 4313-4328

Journal Issue: 10

DOI: 10.1172/JCI98688

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.

Authors with CRIS profile

Involved external institutions

Harvard University United States (USA) (US) Universität zu Köln Germany (DE) Yale University United States (USA) (US) Institut des maladies génétiques Imagine France (FR) King Faisal Specialist Hospital & Research Centre Saudi Arabia (SA) Sindh Institute of Urology and Transplantation Pakistan (PK) National Institute for Biotechnology and Genetic Engineering (NIBGE) / قومی ادارہَ برائے فنونِ حیاتیاتی و مہندسیِ امورِ تناسل Pakistan (PK) Birmingham Women's and Children's NHS Foundation Trust United Kingdom (GB) Universitätsspital Zürich (USZ) Switzerland (CH) Autonomous University of Barcelona (UAB) / Universitat Autònoma de Barcelona Spain (ES) King Saud University (KSU) / جامعة الملك سعود‎‎ Saudi Arabia (SA) Fudan University / 复旦大学 China (CN) Alexandria University / جامعة الإسكندرية‎‎ Egypt (EG) University College London (UCL) United Kingdom (GB) Donostia University Hospital / Donostia Unibertsitate Ospitalea Spain (ES) Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen Germany (DE) Dr. Behçet Uz Childrens Hospital / Dr. Behçet Uz Çocuk Hastalıkları Hastanesi Turkey (TR) University of California Los Angeles (UCLA) United States (USA) (US)

How to cite

APA:

Braun, D.A., Lovric, S., Schapiro, D., Schneider, R., Marquez, J., Asif, M.,... Hildebrandt, F. (2018). Mutations in multiple components of the nuclear pore complex cause nephrotic syndrome. Journal of Clinical Investigation, 128(10), 4313-4328. https://doi.org/10.1172/JCI98688

MLA:

Braun, Daniela A., et al. "Mutations in multiple components of the nuclear pore complex cause nephrotic syndrome." Journal of Clinical Investigation 128.10 (2018): 4313-4328.

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