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

Daniela A Braun; Svjetlana Lovric; David Schapiro; Ronen Schneider; Jonathan Marquez; Maria Asif; Muhammad Sajid Hussain; Ankana Daga; Eugen Widmeier; Jia Rao; Shazia Ashraf; Weizhen Tan; C Patrick Lusk; Amy Kolb; Tilman Jobst-Schwan; Johanna Magdalena Schmidt; Charlotte A Hoogstraten; Kaitlyn Eddy; Thomas M Kitzler; Shirlee Shril; Abubakar Moawia; Kathrin Schrage; Arwa Ishaq A Khayyat; Jennifer A Lawson; Heon Yung Gee; Jillian K Warejko; Tobias Hermle; Amar J Majmundar; Hannah Hugo; Birgit Budde; Susanne Motameny; Janine Altmüller; Angelika Anna Noegel; Hanan M Fathy; Daniel P Gale; Syeda Seema Waseem; Ayaz Khan; Larissa Kerecuk; Seema Hashmi; Nilufar Mohebbi; Robert Ettenger; Erkin Serdaroğlu; Khalid A Alhasan; Mais Hashem; Sara Goncalves; Gema Ariceta; Mercedes Ubetagoyena; Wolfram Antonin; Shahid Mahmood Baig; Fowzan S Alkuraya; Qian Shen; Hong Xu; Corinne Antignac; Richard P Lifton; Shrikant Mane; Peter Nürnberg; Mustafa K Khokha; Friedhelm Hildebrandt

doi:10.1172/JCI98688

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

Journal article

Open access

Peer reviewed

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

Daniela A Braun, Svjetlana Lovric, David Schapiro, Ronen Schneider, Jonathan Marquez, Maria Asif, Muhammad Sajid Hussain, Ankana Daga, Eugen Widmeier, Jia Rao, …

The Journal of clinical investigation, Vol.128(10), pp.4313-4328

01/10/2018

DOI: https://doi.org/10.1172/JCI98688

PMCID: PMC6159964

PMID: 30179222

Abstract

Animals

Cell Line

Disease Models, Animal

Gene Knockdown Techniques

Humans

Nephrotic Syndrome - genetics

Nephrotic Syndrome - metabolism

Nephrotic Syndrome - pathology

Nuclear Pore Complex Proteins - genetics

Nuclear Pore Complex Proteins - metabolism

Xenopus laevis

Xenopus Proteins - genetics

Xenopus Proteins - metabolism

Zebrafish

Zebrafish Proteins - genetics

Zebrafish Proteins - metabolism

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.

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Title: Mutations in multiple components of the nuclear pore complex cause nephrotic syndrome
Creators - without role: Daniela A Braun - University Hospital Münster
Svjetlana Lovric - Boston Children's Hospital
David Schapiro - Boston Children's Hospital
Ronen Schneider - Boston Children's Hospital
Jonathan Marquez - Yale University
Maria Asif - National Institute for Biotechnology and Genetic Engineering
Muhammad Sajid Hussain - University of Cologne
Ankana Daga - Boston Children's Hospital
Eugen Widmeier - Boston Children's Hospital
Jia Rao - Shanghai Kidney Development and Pediatric Kidney Disease Research Center, Shanghai, China
Shazia Ashraf - Boston Children's Hospital
Weizhen Tan - Boston Children's Hospital
C Patrick Lusk - Yale University
Amy Kolb - Boston Children's Hospital
Tilman Jobst-Schwan - Boston Children's Hospital
Johanna Magdalena Schmidt - Boston Children's Hospital
Charlotte A Hoogstraten - Boston Children's Hospital
Kaitlyn Eddy - Boston Children's Hospital
Thomas M Kitzler - Boston Children's Hospital
Shirlee Shril - Boston Children's Hospital
Abubakar Moawia - National Institute for Biotechnology and Genetic Engineering
Kathrin Schrage - University of Cologne
Arwa Ishaq A Khayyat - King Saud University
Jennifer A Lawson - Boston Children's Hospital
Heon Yung Gee - Boston Children's Hospital
Jillian K Warejko - Boston Children's Hospital
Tobias Hermle - Boston Children's Hospital
Amar J Majmundar - Boston Children's Hospital
Hannah Hugo - Boston Children's Hospital
Birgit Budde - University of Cologne
Susanne Motameny - University of Cologne
Janine Altmüller - University of Cologne
Angelika Anna Noegel - University of Cologne
Hanan M Fathy - Faculty
Daniel P Gale - Centre for Nephrology, University College London, Royal Free Hospital, London, United Kingdom
Syeda Seema Waseem - National Institute for Biotechnology and Genetic Engineering
Ayaz Khan - National Institute for Biotechnology and Genetic Engineering
Larissa Kerecuk - Birmingham Children's Hospital
Seema Hashmi - Sindh Institute of Urology and Transplantation
Nilufar Mohebbi - University Hospital of Zurich
Robert Ettenger - University of California, Los Angeles
Erkin Serdaroğlu - Department of Pediatric Nephrology, Dr. Behçet Uz Children's Hospital, Izmir, Turkey
Khalid A Alhasan - King Khalid University Hospital
Mais Hashem - King Abdulaziz City for Science and Technology
Sara Goncalves - Sorbonne Paris Cité
Gema Ariceta - Universitat Autonoma de Barcelona, Hospital Universitari Vall d'Hebron, Pediatric Nephrology, Barcelona, Spain
Mercedes Ubetagoyena - Hospital Universitario Donostia, Pediatric Nephrology, Donostia-San Sebastian, Spain
Wolfram Antonin - RWTH Aachen University
Shahid Mahmood Baig - National Institute for Biotechnology and Genetic Engineering
Fowzan S Alkuraya - King Abdulaziz City for Science and Technology
Qian Shen - Shanghai Kidney Development and Pediatric Kidney Disease Research Center, Shanghai, China
Hong Xu - Shanghai Kidney Development and Pediatric Kidney Disease Research Center, Shanghai, China
Corinne Antignac - Assistance Publique – Hôpitaux de Paris
Richard P Lifton - Rockefeller University
Shrikant Mane - Yale University
Peter Nürnberg - University of Cologne
Mustafa K Khokha - Yale University
Friedhelm Hildebrandt - Boston Children's Hospital
Publication Details: The Journal of clinical investigation, Vol.128(10), pp.4313-4328
Grant note: T32 GM007223 / NIGMS NIH HHS S10 OD018521 / NIH HHS T32 GM007205 / NIGMS NIH HHS T32 DK007726 / NIDDK NIH HHS P30 DK079310 / NIDDK NIH HHS R01 DK076683 / NIDDK NIH HHS
Identifiers: 9948448608331
Academic Unit: King Faisal University; King Saud University; King Khalid University; Alfaisal University
Language: English
Resource Type: Journal article