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


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.

SUBMITTER: Braun DA 

PROVIDER: S-EPMC6159964 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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

Braun Daniela A DA   Lovric Svjetlana S   Schapiro David D   Schneider Ronen R   Marquez Jonathan J   Asif Maria M   Hussain Muhammad Sajid MS   Daga Ankana A   Widmeier Eugen E   Rao Jia J   Ashraf Shazia S   Tan Weizhen W   Lusk C Patrick CP   Kolb Amy A   Jobst-Schwan Tilman T   Schmidt Johanna Magdalena JM   Hoogstraten Charlotte A CA   Eddy Kaitlyn K   Kitzler Thomas M TM   Shril Shirlee S   Moawia Abubakar A   Schrage Kathrin K   Khayyat Arwa Ishaq A AIA   Lawson Jennifer A JA   Gee Heon Yung HY   Warejko Jillian K JK   Hermle Tobias T   Majmundar Amar J AJ   Hugo Hannah H   Budde Birgit B   Motameny Susanne S   Altmüller Janine J   Noegel Angelika Anna AA   Fathy Hanan M HM   Gale Daniel P DP   Waseem Syeda Seema SS   Khan Ayaz A   Kerecuk Larissa L   Hashmi Seema S   Mohebbi Nilufar N   Ettenger Robert R   Serdaroğlu Erkin E   Alhasan Khalid A KA   Hashem Mais M   Goncalves Sara S   Ariceta Gema G   Ubetagoyena Mercedes M   Antonin Wolfram W   Baig Shahid Mahmood SM   Alkuraya Fowzan S FS   Shen Qian Q   Xu Hong H   Antignac Corinne C   Lifton Richard P RP   Mane Shrikant S   Nürnberg Peter P   Khokha Mustafa K MK   Hildebrandt Friedhelm F  

The Journal of clinical investigation 20180904 10


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 NU  ...[more]

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