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

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, Svjetlana Lovric, Daniela A. Braun, Heon Yung Gee, David Schapiro, Amar J. Majmundar, Carolin E. Sadowski, Werner L. Pabst, Ankana Daga, Amelie T. Ven, Johanna M. Schmidt, Boon Chuan Low, Anjali Bansal Gupta, Brajendra K. Tripathi, Jenny Wong, Kirk Campbell, Kay Metcalfe, Denny Schanze, Tetsuya Niihori, Hiroshi Kaito, Kandai Nozu, Hiroyasu Tsukaguchi, Ryojiro Tanaka, Kiyoshi Hamahira, Yasuko Kobayashi, Takumi Takizawa, Ryo Funayama, Keiko Nakayama, Yoko Aoki, Naonori Kumagai, Kazumoto Iijima, Henry Fehrenbach, Jameela A. Kari, Sherif El Desoky, Sawsan Jalalah, Radovan Bogdanovic, Nataša Stajić, Hildegard Zappel, Assel Rakhmetova, Sharon-Rose Wassmer, Therese Jungraithmayr, Juergen Strehlau, Aravind Selvin Kumar, Arvind Bagga, Neveen A. Soliman, Shrikant M. Mane, Lewis Kaufman, Douglas R. Lowy, Mohamad A. Jairajpuri, Richard P. Lifton, York Pei, Martin Zenker, Shigeo Kure () and Friedhelm Hildebrandt ()
Additional contact information
Shazia Ashraf: Harvard Medical School
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
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
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
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
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

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04193-w

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