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

Item Type:	Article
Title:	Mutations in multiple components of the nuclear pore complex cause nephrotic syndrome
Creators Name:	Braun, D.A. and Lovric, S. and Schapiro, D. and Schneider, R. and Marquez, J. and Asif, M. and Hussain, M.S. and Daga, A. and Widmeier, E. and Rao, J. and Ashraf, S. and Tan, W. and Lusk, C.P. and Kolb, A. and Jobst-Schwan, T. and Schmidt, J.M. and Hoogstraten, C.A. and Eddy, K. and Kitzler, T.M. and Shril, S. and Moawia, A. and Schrage, K. and Khayyat, A.I.A. and Lawson, J.A. and Gee, H.Y. and Warejko, J.K. and Hermle, T. and Majmundar, A.J. and Hugo, H. and Budde, B. and Motameny, S. and Altmüller, J. and Noegel, A. A. and Fathy, H.M. and Gale, D.P. and Waseem, S.S. and Khan, A. and Kerecuk, L. and Hashmi, S. and Mohebbi, N. and Ettenger, R. and Serdaroğlu, E. and Alhasan, K.A. and Hashem, M. and Goncalves, S. and Ariceta, G. and Ubetagoyena, M. and Antonin, W. and Baig, S.M. and Alkuraya, F.S. and Shen, Q. and Xu, H. and Antignac, C. and Lifton, R.P. and Mane, S. and Nürnberg, P. and Khokha, M.K. and Hildebrandt, F.
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.
Keywords:	Animal Disease Models, Cell Line, Gene Knockdown Techniques, Nephrotic Syndrome, Nuclear Pore Complex Proteins, Xenopus Proteins, Zebrafish Proteins, Animals, Xenopus laevis, Zebrafish
Source:	Journal of Clinical Investigation
ISSN:	0021-9738
Publisher:	American Society for Clinical Investigation
Volume:	128
Number:	10
Page Range:	4313-4328
Date:	1 October 2018
Official Publication:	https://doi.org/10.1172/JCI98688
PubMed:	View item in PubMed

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