Publications

Mutations in nuclear pore genes NUP93, NUP205, and XPO5 cause steroid resistant nephrotic syndrome

Braun, D.A., Sadowski, C.E., Kohl, S. et al.

Nucleoporins (NUPs) are essential components of the nuclear pore complex (NPC). Only a few diseases have been attributed to NPC dysfunction. Steroid resistant nephrotic syndrome (SRNS), a frequent cause of chronic kidney disease, is caused by dysfunction of glomerular podocytes. Here we identify in 8 families with SRNS mutations of NUP93, its interaction partner NUP205, or exportin5 (XPO5) as a hitherto unrecognized monogenic cause of SRNS. NUP93 mutations caused disrupted NPC assembly. NUP93 knockdown reduced the presence of NUP205 in the NPC and, reciprocally, a NUP205 mutation abrogated NUP93 interaction. We demonstrate that NUP93 and XPO5 interact with the signaling protein SMAD4, and that NUP93 mutations abrogated interaction with SMAD4. Significantly, NUP93 mutations interfered with BMP7-induced SMAD transcriptional reporter activity. We hereby demonstrate that mutations of NUPs cause a distinct renal disease, and reveal SMAD signaling as a novel disease mechanism of SRNS, opening a potential new avenue for treatment.

Citation

Braun, D.A., Sadowski, C.E., Kohl, S. et al. "Mutations in nuclear pore genes NUP93, NUP205, and XPO5 cause steroid resistant nephrotic syndrome" Nature Genetics (2016): 457–65