LAUSR

https://doi.org/10.1172/JCI98688 (2018) it was surprising that germline mutations in genes that are expressed in every cell of the human body give rise to a cell-specific phenotype Mutations in four genes that encode components of the outer ring subunits of the nuclear pore complex (NPC) are associated with steroid-resistant nephrotic syndrome (SRNS), say researchers. Podocytes are the critical site of injury in SRNS and although >50 monogenic causes have been identified, many cases are unexplained. Previous studies have shown that mutations in NUP93 and NUP205, which encode proteins of the inner ring subunit of the NPC, cause SRNS. “NPC proteins are ubiquitously expressed and play an essential role in every eukaryotic cell, so it was surprising that germline mutations in genes that are expressed in every cell of the human body give rise to a cell-specific phenotype,” says Friedhelm Hildebrandt, an author on the new paper. In their latest study, Braun et al. further investigated the functional link between alterations in NPC proteins and podocyte injury. They performed whole-exome sequencing in 160 families with SRNS. They excluded mutations in known SRNS genes and used homozygosity mapping in consanguineous families to identify mutations in four genes encoding components of the outer ring subunits of the NPC — NUP107, NUP85, NUP133 and NUP160 — that cause SRNS. The researchers used co-immunoprecipitation experiments to show that particular pathogenic alleles of NUP107, NUP85, NUP160 and NUP133 weaken the protein–protein interactions between components of the NPC. The researchers used the CRISPR–Cas9 system to generate stable zebrafish lines carrying different alleles of NUP107 and NUP85 and found that fish with two null mutations died early in n e P H r Ot i c S Y n D r O M e