Mutations in multiple components of the nuclear pore complex cause nephrotic syndrome
Mutations in multiple components of the nuclear pore complex cause nephrotic syndrome
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DOI：
10.1172/jci98688
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发表时间：
2018-10-01
影响因子：
15.9
通讯作者：
Hildebrandt, Friedhelm
中科院分区：
文献类型：
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作者：
Braun, Daniela A.;Lovric, Svjetlana;Hildebrandt, Friedhelm
类固醇抵抗性肾病综合征（SRNS）几乎总是进展为终末期肾脏疾病。虽然已有50多种SRNS的单基因原因被描述，但大部分SRNS仍未得到解释。最近，研究发现编码核孔复合物（NPC）内环亚基2个蛋白的NUP93和NUP205突变可引起SRNS。在此，我们描述了在13个SRNS家族中编码NPC外环4个组分的基因突变，即NUP107、NUP85、NUP133和NUP160。通过共免疫沉淀实验，我们发现某些致病等位基因削弱了邻近NPC亚基之间的相互作用。我们证明，在非洲爪蟾中，morpholino敲低nup107、nup85或nup133会破坏肾小球的发生。WT mRNA的重新表达，而不是反映SRNS患者突变的mRNA的重新表达，减轻了这种表型。我们进一步发现，CRISPR/Cas9敲除足细胞中的NUP107、NUP85或NUP133可激活Cdc42，这是SRNS发病机制的一个重要效应因子。CRISPR/Cas9敲除斑马鱼的nup107或nup85可导致发育异常和早期死亡。相比之下，nup107的框架内突变不会影响存活，因此模仿了在人类中看到的等位基因效应。总之，我们在这里发现编码鼻咽癌外环亚基组分的4个基因突变导致SRNS，从而进一步证明这些必需基因的特异性亚形态突变导致不同的器官特异性表型。
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.