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

Nat Genet. 2016 Apr;48(4):457-65. doi: 10.1038/ng.3512.

Daniela A Braun ¹, Carolin E Sadowski ¹, Stefan Kohl ¹, Svjetlana Lovric ¹, Susanne A Astrinidis ², Werner L Pabst ¹, Heon Yung Gee ¹ ³, Shazia Ashraf ¹, Jennifer A Lawson ¹, Shirlee Shril ¹, Merlin Airik ¹, Weizhen Tan ¹, David Schapiro ¹, Jia Rao ¹, Won-Il Choi ¹, Tobias Hermle ¹, Markus J Kemper ⁴, Martin Pohl ⁵, Fatih Ozaltin ⁶ ⁷ ⁸, Martin Konrad ⁹, Radovan Bogdanovic ¹⁰, Rainer Büscher ¹¹, Udo Helmchen ¹², Erkin Serdaroglu ¹³, Richard P Lifton ¹⁴ ¹⁵, Wolfram Antonin ², Friedhelm Hildebrandt ¹ ¹⁵

Affiliations

1 Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
2 Friedrich Miescher Laboratory, Max Planck Society, Tübingen, Germany.
3 Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Korea.
4 Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
5 Department of Pediatrics and Adolescent Medicine, University of Freiburg Medical Center, Freiburg, Germany.
6 Department of Pediatric Nephrology, Hacettepe University Faculty of Medicine, Ankara, Turkey.
7 Nephrogenetics Laboratory, Hacettepe University, Ankara, Turkey.
8 Center for Biobanking and Genomics, Hacettepe University, Ankara, Turkey.
9 Department of General Pediatrics, University Hospital Münster, Münster, Germany.
10 Medical Faculty, University of Belgrade, Belgrade, Serbia.
11 Department of Pediatrics II, Pediatric Nephrology, University of Duisburg-Essen, Essen, Germany.
12 Institute of Pathology, Kidney Registry, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
13 Department of Pediatric Nephrology, Dr. Behçet Uz Children Hospital, Izmir, Turkey.
14 Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.
15 Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

PMID: 26878725 DOI: 10.1038/ng.3512

Abstract

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.

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