Mutations in multiple components of the nuclear pore complex cause nephrotic syndrome
| Autor: | Larissa Kerecuk, Tilman Jobst-Schwan, Weizhen Tan, Khalid A. Alhasan, Mais Hashem, Shrikant Mane, Jonathan Marquez, Seema Hashmi, Shahid Mahmood Baig, Svjetlana Lovric, Heon Yung Gee, Kaitlyn Eddy, Johanna Magdalena Schmidt, Sara Gonçalves, Jillian K. Warejko, Ayaz Khan, Mustafa K. Khokha, Charlotte A. Hoogstraten, Hannah Hugo, Mercedes Ubetagoyena, Birgit Budde, M. Asif, Amar J. Majmundar, Jennifer A. Lawson, Qian Shen, Gema Ariceta, Angelika A. Noegel, Tobias Hermle, Eugen Widmeier, Susanne Motameny, Nilufar Mohebbi, Friedhelm Hildebrandt, Janine Altmüller, Richard P. Lifton, Kathrin Schrage, Thomas M. Kitzler, Muhammad Sajid Hussain, Amy Kolb, Hanan M. Fathy, Arwa Ishaq A. Khayyat, Ankana Daga, Robert B. Ettenger, David Schapiro, Daniela A. Braun, Erkin Serdaroglu, Shirlee Shril, Hong Xu, Syeda Seema Waseem, Fowzan S. Alkuraya, Jia Rao, Ronen Schneider, C. Patrick Lusk, Daniel P. Gale, Corinne Antignac, Peter Nürnberg, Wolfram Antonin, Shazia Ashraf, Abubakar Moawia |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Nephrotic Syndrome Protein subunit Xenopus Proteins medicine.disease_cause Cell Line Xenopus laevis 03 medical and health sciences medicine Animals Humans Nuclear pore Allele Gene Zebrafish Genetics Mutation biology Effector General Medicine Zebrafish Proteins biology.organism_classification Phenotype Nuclear Pore Complex Proteins Disease Models Animal Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11] 030104 developmental biology Gene Knockdown Techniques |
| Zdroj: | Journal of Clinical Investigation, 128, 10, pp. 4313-4328 Journal of Clinical Investigation, 128, 4313-4328 |
| ISSN: | 1558-8238 0021-9738 |
| DOI: | 10.1172/jci98688 |
| Popis: | Item does not contain fulltext 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. |
| Databáze: | OpenAIRE |
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