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J Clin Invest January 1, 2018; 128 (10): 4313-4328.
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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 , Altmüller J , Noegel AA , Fathy HM , Gale DP , Waseem SS , Khan A , Kerecuk L , Hashmi S , Mohebbi N , Ettenger R , Serdaroğlu 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 , Nürnberg P , Khokha MK , Hildebrandt F .

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.

PubMed ID: 30179222
PMC ID: PMC6159964
Article link: J Clin Invest
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: cdc42 nup107 nup133 nup155 nup160 nup205 nup37 nup85 nup93 pax8
Morpholinos: nup107 MO1 nup133 MO1 nup155 MO1 nup85 MO1

Disease Ontology terms: nephrotic syndrome [+]
References [+] :
Ahmad, Genetic heterogeneity in Pakistani microcephaly families revisited. 2018, Pubmed