Mutations in multiple components of the nuclear pore complex cause nephrotic syndrome

J Clin Invest. 2018 Oct 1;128(10):4313-4328. doi: 10.1172/JCI98688.

Daniela A Braun ¹ ², Svjetlana Lovric ¹, David Schapiro ¹, Ronen Schneider ¹, Jonathan Marquez ³, Maria Asif ⁴ ⁵ ⁶, Muhammad Sajid Hussain ⁴ ⁵ ⁷, Ankana Daga ¹, Eugen Widmeier ¹, Jia Rao ⁸ ⁹, Shazia Ashraf ¹, Weizhen Tan ¹, C Patrick Lusk ¹⁰, Amy Kolb ¹, Tilman Jobst-Schwan ¹, Johanna Magdalena Schmidt ¹, Charlotte A Hoogstraten ¹, Kaitlyn Eddy ¹, Thomas M Kitzler ¹, Shirlee Shril ¹, Abubakar Moawia ⁴ ⁵ ⁶, Kathrin Schrage ⁵, Arwa Ishaq A Khayyat ⁵ ¹¹, Jennifer A Lawson ¹, Heon Yung Gee ¹, Jillian K Warejko ¹, Tobias Hermle ¹, Amar J Majmundar ¹, Hannah Hugo ¹, Birgit Budde ⁴, Susanne Motameny ⁴, Janine Altmüller ⁴ ⁷ ¹², Angelika Anna Noegel ⁵ ⁷ ¹³, Hanan M Fathy ¹⁴, Daniel P Gale ¹⁵, Syeda Seema Waseem ⁴ ⁵ ⁶, Ayaz Khan ⁶, Larissa Kerecuk ¹⁶, Seema Hashmi ¹⁷, Nilufar Mohebbi ¹⁸, Robert Ettenger ¹⁹, Erkin Serdaroğlu ²⁰, Khalid A Alhasan ²¹, Mais Hashem ²² ²³ ²⁴, Sara Goncalves ²⁵ ²⁶, Gema Ariceta ²⁷, Mercedes Ubetagoyena ²⁸, Wolfram Antonin ²⁹, Shahid Mahmood Baig ⁶, Fowzan S Alkuraya ²² ²³ ²⁴, Qian Shen ⁸ ⁹, Hong Xu ⁸ ⁹, Corinne Antignac ²⁵ ²⁶ ³⁰, Richard P Lifton ³¹ ³², Shrikant Mane ³¹, Peter Nürnberg ⁴ ⁷ ¹³, Mustafa K Khokha ³, Friedhelm Hildebrandt ¹

Affiliations

1 Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
2 Department of Internal Medicine D, University Hospital of Münster, Münster, Germany.
3 Pediatric Genomics Discovery Program, Department of Pediatrics and Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.
4 Cologne Center for Genomics, University of Cologne, Cologne, Germany.
5 Institute of Biochemistry I, Medical Faculty, University of Cologne, Cologne, Germany.
6 Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering, Pakistan Institute of Engineering and Applied Sciences, Faisalabad, Pakistan.
7 Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
8 Department of Nephrology, Children's Hospital of Fudan University, Shanghai, China.
9 Shanghai Kidney Development and Pediatric Kidney Disease Research Center, Shanghai, China.
10 Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut, USA.
11 Biochemistry Department, King Saud University, Riyadh, Saudi Arabia.
12 Institute of Human Genetics, University of Cologne, Cologne, Germany.
13 Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
14 Pediatric Nephrology Unit, Alexandria Faculty of Medicine, University of Alexandria, Alexandria, Egypt.
15 Centre for Nephrology, University College London, Royal Free Hospital, London, United Kingdom.
16 Birmingham Children's Hospital NHS Foundation Trust, Birmingham, United Kingdom.
17 Department of Pediatric Nephrology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan.
18 Division of Nephrology, University Hospital Zurich, Zurich, Switzerland.
19 Department of Pediatrics, University of California, Los Angeles, California.
20 Department of Pediatric Nephrology, Dr. Behçet Uz Children's Hospital, Izmir, Turkey.
21 Pediatric Department, College of Medicine, King Saud University and King Khalid University Hospital, Riyadh, Saudi Arabia.
22 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
23 Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
24 Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
25 Laboratory of Hereditary Kidney Diseases, INSERM UMR1163, Imagine, Institute, Paris, France.
26 Université Paris Descartes-Sorbonne Paris Cité, Imagine, Institute, Paris, France.
27 Universitat Autonoma de Barcelona, Hospital Universitari Vall d'Hebron, Pediatric Nephrology, Barcelona, Spain.
28 Hospital Universitario Donostia, Pediatric Nephrology, Donostia-San Sebastian, Spain.
29 Institute of Biochemistry and Molecular Cell Biology, Medical School, RWTH Aachen University, 52074 Aachen, Germany.
30 Department of Genetics, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
31 Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.
32 Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, New York, USA.

PMID: 30179222 DOI: 10.1172/JCI98688

Abstract

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.

Keywords

Genetics; Monogenic diseases; Nephrology.

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