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

TitleMutations in nuclear pore genes NUP93, NUP205 and XPO5 cause steroid-resistant nephrotic syndrome.
Publication TypeJournal Article
Year of Publication2016
AuthorsBraun, DA, Sadowski, CE, Kohl, S, Lovric, S, Astrinidis, SA, Pabst, WL, Gee, HYung, Ashraf, S, Lawson, JA, Shril, S, Airik, M, Tan, W, Schapiro, D, Rao, J, Choi, W-I, Hermle, T, Kemper, MJ, Pohl, M, Ozaltin, F, Konrad, M, Bogdanovic, R, Büscher, R, Helmchen, U, Serdaroglu, E, Lifton, RP, Antonin, W, Hildebrandt, F
JournalNat Genet
Date Published2016 Apr
KeywordsAge of Onset, Amino Acid Sequence, Animals, Cell Movement, Cell Proliferation, Cells, Cultured, Child, Child, Preschool, Drug Resistance, Female, Genes, Recessive, Genetic Association Studies, Genetic Linkage, HEK293 Cells, Humans, Infant, Karyopherins, Male, Mice, Molecular Sequence Data, Mutation, Nephrotic Syndrome, Nuclear Pore Complex Proteins, Oxidative Stress, Podocytes, Sequence Analysis, DNA, Steroids, Xenopus laevis

Nucleoporins 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 eight families with SRNS mutations in NUP93, its interaction partner NUP205 or XPO5 (encoding exportin 5) as hitherto unrecognized monogenic causes of SRNS. NUP93 mutations caused disrupted NPC assembly. NUP93 knockdown reduced the presence of NUP205 in the NPC, and, reciprocally, a NUP205 alteration abrogated NUP93 interaction. We demonstrate that NUP93 and exportin 5 interact with the signaling protein SMAD4 and that NUP93 mutations abrogated interaction with SMAD4. Notably, NUP93 mutations interfered with BMP7-induced SMAD transcriptional reporter activity. We hereby demonstrate that mutations of NUP genes cause a distinct renal disease and identify aberrant SMAD signaling as a new disease mechanism of SRNS, opening a potential new avenue for treatment.

Alternate JournalNat. Genet.
PubMed ID26878725
PubMed Central IDPMC4811732
Grant ListUM1 HG006504 / HG / NHGRI NIH HHS / United States
DK076683 / DK / NIDDK NIH HHS / United States
P30 DK079310 / DK / NIDDK NIH HHS / United States
R01 DK076683 / DK / NIDDK NIH HHS / United States
R01 DK068306 / DK / NIDDK NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
T32 DK007726 / DK / NIDDK NIH HHS / United States