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

Author

Listed:
  • Shazia Ashraf

    (Harvard Medical School
    Jamia Millia Islamia)

  • Hiroki Kudo

    (Tohoku University School of Medicine)

  • Jia Rao

    (Harvard Medical School)

  • Atsuo Kikuchi

    (Tohoku University School of Medicine)

  • Eugen Widmeier

    (Harvard Medical School)

  • Jennifer A. Lawson

    (Harvard Medical School)

  • Weizhen Tan

    (Harvard Medical School)

  • Tobias Hermle

    (Harvard Medical School)

  • Jillian K. Warejko

    (Harvard Medical School)

  • Shirlee Shril

    (Harvard Medical School)

  • Merlin Airik

    (Harvard Medical School)

  • Tilman Jobst-Schwan

    (Harvard Medical School)

  • Svjetlana Lovric

    (Harvard Medical School)

  • Daniela A. Braun

    (Harvard Medical School)

  • Heon Yung Gee

    (Harvard Medical School
    Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine)

  • David Schapiro

    (Harvard Medical School)

  • Amar J. Majmundar

    (Harvard Medical School)

  • Carolin E. Sadowski

    (Harvard Medical School)

  • Werner L. Pabst

    (Harvard Medical School)

  • Ankana Daga

    (Harvard Medical School)

  • Amelie T. Ven

    (Harvard Medical School)

  • Johanna M. Schmidt

    (Harvard Medical School)

  • Boon Chuan Low

    (National University of Singapore
    National University of Singapore)

  • Anjali Bansal Gupta

    (National University of Singapore)

  • Brajendra K. Tripathi

    (National Institutes of Health)

  • Jenny Wong

    (Icahn School of Medicine at Mount Sinai)

  • Kirk Campbell

    (Icahn School of Medicine at Mount Sinai)

  • Kay Metcalfe

    (Manchester Academic Health Science Centre)

  • Denny Schanze

    (University Hospital Magdeburg)

  • Tetsuya Niihori

    (Tohoku University School of Medicine)

  • Hiroshi Kaito

    (Kobe University Graduate School of Medicine)

  • Kandai Nozu

    (Kobe University Graduate School of Medicine)

  • Hiroyasu Tsukaguchi

    (Kansai Medical University)

  • Ryojiro Tanaka

    (Hyogo Prefectural Kobe Children’s Hospital)

  • Kiyoshi Hamahira

    (Himeji Red Cross Hospital)

  • Yasuko Kobayashi

    (Gunma University Graduate School of Medicine
    University of Bristol)

  • Takumi Takizawa

    (Gunma University Graduate School of Medicine)

  • Ryo Funayama

    (Tohoku University Graduate School of Medicine)

  • Keiko Nakayama

    (Tohoku University Graduate School of Medicine)

  • Yoko Aoki

    (Tohoku University School of Medicine)

  • Naonori Kumagai

    (Tohoku University School of Medicine)

  • Kazumoto Iijima

    (Kobe University Graduate School of Medicine)

  • Henry Fehrenbach

    (Children’s Hospital)

  • Jameela A. Kari

    (King Abdulaziz University)

  • Sherif El Desoky

    (King Abdulaziz University)

  • Sawsan Jalalah

    (King Abdulaziz University)

  • Radovan Bogdanovic

    (University of Belgrade, Faculty of Medicine)

  • Nataša Stajić

    (University of Belgrade, Faculty of Medicine)

  • Hildegard Zappel

    (University of Göttingen)

  • Assel Rakhmetova

    (Asfendiyarov Kazakh National Medical University)

  • Sharon-Rose Wassmer

    (Luzerner Kantonsspital)

  • Therese Jungraithmayr

    (University Medical Center Innsbruck)

  • Juergen Strehlau

    (Hannover Medical School)

  • Aravind Selvin Kumar

    (TN Dr.M.G.R. Medical University)

  • Arvind Bagga

    (All India Institute of Medical Sciences)

  • Neveen A. Soliman

    (Cairo University)

  • Shrikant M. Mane

    (Yale University School of Medicine)

  • Lewis Kaufman

    (Icahn School of Medicine at Mount Sinai)

  • Douglas R. Lowy

    (National Institutes of Health)

  • Mohamad A. Jairajpuri

    (Jamia Millia Islamia)

  • Richard P. Lifton

    (Yale University School of Medicine
    Laboratory of Human Genetics and Genomics, The Rockefeller University)

  • York Pei

    (University Health Network, and University of Toronto)

  • Martin Zenker

    (University Hospital Magdeburg)

  • Shigeo Kure

    (Tohoku University School of Medicine)

  • Friedhelm Hildebrandt

    (Harvard Medical School)

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.

Suggested Citation

  • Shazia Ashraf & Hiroki Kudo & Jia Rao & Atsuo Kikuchi & Eugen Widmeier & Jennifer A. Lawson & Weizhen Tan & Tobias Hermle & Jillian K. Warejko & Shirlee Shril & Merlin Airik & Tilman Jobst-Schwan & Sv, 2018. "Mutations in six nephrosis genes delineate a pathogenic pathway amenable to treatment," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04193-w
    DOI: 10.1038/s41467-018-04193-w
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