Mutations in six nephrosis genes delineate a pathogenic pathway amenable to treatment

Ashraf S, Kudo H, Rao J, Kikuchi A, Widmeier E, Lawson JA, Tan W, Hermle T, Warejko JK, Shril S, Airik M, Jobst-Schwan T, Lovric S, Braun DA, Gee HY, Schapiro D, Majmundar AJ, Sadowski CE, Pabst WL, Daga A, Van Der Ven AT, Schmidt JM, Low BC, Gupta AB, Tripathi BK, Wong J, Campbell K, Metcalfe K, Schanze D, Niihori T, Kaito H, Nozu K, Tsukaguchi H, Tanaka R, Hamahira K, Kobayashi Y, Takizawa T, Funayama R, Nakayama K, Aoki Y, Kumagai N, Iijima K, Fehrenbach H, Kari JA, El Desoky S, Jalalah S, Bogdanovic R, Stajic N, Zappel H, Rakhmetova A, Wassmer SR, Jungraithmayr T, Strehlau J, Kumar AS, Bagga A, Soliman NA, Mane SM, Kaufman L, Lowy DR, Jairajpuri MA, Lifton RP, Pei Y, Zenker M, Kure S, Hildebrandt F (2018)

Publication Type: Journal article

Publication year: 2018

Journal

Book Volume: 9

Article Number: 1960

Journal Issue: 1

DOI: 10.1038/s41467-018-04193-w

Abstract

No efficient treatment exists for nephrotic syndrome (NS), a frequent cause of chronic kidney disease. Here we show mutations in six different genes (MAGI2, TNS2, DLC1, CDK20, ITSN1, ITSN2) as causing NS in 17 families with partially treatment-sensitive NS (pTSNS). These proteins interact and we delineate their roles in Rho-like small GTPase (RLSG) activity, and demonstrate deficiency for mutants of pTSNS patients. We find that CDK20 regulates DLC1. Knockdown of MAGI2, DLC1, or CDK20 in cultured podocytes reduces migration rate. Treatment with dexamethasone abolishes RhoA activation by knockdown of DLC1 or CDK20 indicating that steroid treatment in patients with pTSNS and mutations in these genes is mediated by this RLSG module. Furthermore, we discover ITSN1 and ITSN2 as podocytic guanine nucleotide exchange factors for Cdc42. We generate Itsn2-L knockout mice that recapitulate the mild NS phenotype. We, thus, define a functional network of RhoA regulation, thereby revealing potential therapeutic targets.

Authors with CRIS profile

Involved external institutions

Harvard University United States (USA) (US) Tohoku University Japan (JP) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) Yale University United States (USA) (US) University of Belgrade / Универзитет у Београду Serbia (RS) All India Institute of Medical Sciences India (IN) Icahn School of Medicine at Mount Sinai United States (USA) (US) Kazakh National Medical University (KAZNMU) / Қазақ ұлттық медицина университеті / Казахский национальный медицинский университет Kazakhstan (KZ) National Cancer Institute (NCI) United States (USA) (US) University Health Network (UHN) Canada (CA) Himeji Red Cross Hospital / 姫路赤十字病院 Japan (JP) King Abdulaziz University (KAU) / جامعة الملك عبد العزيز Saudi Arabia (SA) Universitätsklinikum Magdeburg A.ö.R. Germany (DE) Kobe University / 神戸大学 Japan (JP) Jamia Millia Islamia India (IN) Medizinische Universität Innsbruck Austria (AT) National University of Singapore (NUS) Singapore (SG) Cairo University Egypt (EG) Hyogo Prefectural Kobe Children's Hospital / 兵庫県立こども病院 Japan (JP) Klinikum Memmingen Germany (DE) Georg-August-Universität Göttingen Germany (DE) Tamil Nadu Dr. M.G.R. Medical University (TNMGRMU) / தமிழ்நாடு டாக்டர் எம்.ஜி.ஆர். மருத்துவப் பல்கலைக்கழகம் India (IN) Luzerner Kantonsspital (LUKS) Switzerland (CH) Central Manchester University Hospitals United Kingdom (GB) Gunma University Japan (JP) Kansai Medical University Japan (JP)

How to cite

APA:

Ashraf, S., Kudo, H., Rao, J., Kikuchi, A., Widmeier, E., Lawson, J.A.,... Hildebrandt, F. (2018). Mutations in six nephrosis genes delineate a pathogenic pathway amenable to treatment. Nature Communications, 9(1). https://doi.org/10.1038/s41467-018-04193-w

MLA:

Ashraf, Shazia, et al. "Mutations in six nephrosis genes delineate a pathogenic pathway amenable to treatment." Nature Communications 9.1 (2018).

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