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. Van Der 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; Friedhelm Hildebrandt

doi:10.1038/s41467-018-04193-w

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 DagaAmelie T. Van Der 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, Friedhelm Hildebrandt

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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.

Original language	English
Article number	1960
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-04193-w
Publication status	Published - 2018 Dec 1

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Ashraf, S., Kudo, H., Rao, J., Kikuchi, A., Widmeier, E., Lawson, J. A., Tan, W., Hermle, T., Warejko, J. K., Shril, S., Airik, M., Jobst-Schwan, T., Lovric, S., Braun, D. A., Gee, H. Y., Schapiro, D., Majmundar, A. J., Sadowski, C. E., Pabst, W. L., ... Hildebrandt, F. (2018). Mutations in six nephrosis genes delineate a pathogenic pathway amenable to treatment. Nature Communications, 9(1), Article 1960. https://doi.org/10.1038/s41467-018-04193-w

@article{c1136d1f8f224cfa978c9b3d5c2be229,

title = "Mutations in six nephrosis genes delineate a pathogenic pathway amenable to treatment",

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.",

author = "Shazia Ashraf and Hiroki Kudo and Jia Rao and Atsuo Kikuchi and Eugen Widmeier and Lawson, {Jennifer A.} and Weizhen Tan and Tobias Hermle and Warejko, {Jillian K.} and Shirlee Shril and Merlin Airik and Tilman Jobst-Schwan and Svjetlana Lovric and Braun, {Daniela A.} and Gee, {Heon Yung} and David Schapiro and Majmundar, {Amar J.} and Sadowski, {Carolin E.} and Pabst, {Werner L.} and Ankana Daga and {Van Der Ven}, {Amelie T.} and Schmidt, {Johanna M.} and Low, {Boon Chuan} and Gupta, {Anjali Bansal} and Tripathi, {Brajendra K.} and Jenny Wong and Kirk Campbell and Kay Metcalfe and Denny Schanze and Tetsuya Niihori and Hiroshi Kaito and Kandai Nozu and Hiroyasu Tsukaguchi and Ryojiro Tanaka and Kiyoshi Hamahira and Yasuko Kobayashi and Takumi Takizawa and Ryo Funayama and Keiko Nakayama and Yoko Aoki and Naonori Kumagai and Kazumoto Iijima and Henry Fehrenbach and Kari, {Jameela A.} and {El Desoky}, Sherif and Sawsan Jalalah and Radovan Bogdanovic and Nata{\v s}a Staji{\'c} and Hildegard Zappel and Assel Rakhmetova and Wassmer, {Sharon Rose} and Therese Jungraithmayr and Juergen Strehlau and Kumar, {Aravind Selvin} and Arvind Bagga and Soliman, {Neveen A.} and Mane, {Shrikant M.} and Lewis Kaufman and Lowy, {Douglas R.} and Jairajpuri, {Mohamad A.} and Lifton, {Richard P.} and York Pei and Martin Zenker and Shigeo Kure and Friedhelm Hildebrandt",

note = "Funding Information: We are grateful to study individuals for their contribution. We acknowledge the Yale Center for Mendelian Genomics for whole exome sequencing. This research was supported by grants from the National Institutes of Health to F.H. (DK076683) and by the Howard Hughes Medical Institute to F.H. F.H. is the William E. Harmon Professor of Pediatrics. E.W. is supported by the German National Academy of Sciences Leopoldina (LPDS-2015-07). W.T. is supported by the ASN Foundation for Kidney Research. T.H. is supported by the DFG-fellowship (HE 7456/1-1). T.J.S. is supported by the Deutsche Forschungsgemeinschaft (Jo 1324/1-1). H.Y.G. is supported by the National Research Foundation of Korea, Ministry of Science, ICT, and Future planning (2015R1D1A1A01056685) and faculty seed money from the Yonsei University College of Medicine (2015-32-0047). A.T.v.d.V. is supported by the DFG-fellowship (VE 196/1-1). We thank Yoko Chiba, Kumi Ito, Miyuki Tsuda, Mami Kikuchi, Makiko Nakagawa, Yoko Tateda and Kiyotaka Kuroda for their technical assistance. This work was supported by grants (17ek0109151h0003 and 17ek0109278h0001) from Japan Agency for Medical Research and Development (AMED) to S.K. We acknowledge the support of the Biomedical Research Unit of Tohoku University Hospital and the Biomedical Research Core and the Institute for Animal Experimentation of Tohoku University Graduate School of Medicine. N.A.S is supported by the Egyptian Group for Orphan Renal Diseases (EGORD). M.A.J. is supported by Department of Science and Technology, Govt. of India (DST-SERB). M.Z. was supported by the Deutsche Forschungsgemeinschaft (SFB423). Funding Information: This research was supported by grants from the National Institutes of Health to F.H. (DK076683) and by the Howard Hughes Medical Institute to F.H. F.H. is the William E. Harmon Professor of Pediatrics. E.W. is supported by the German National Academy of Sciences Leopoldina (LPDS-2015-07). W.T. is supported by the ASN Foundation for Kidney Research. T.H. is supported by the DFG-fellowship (HE 7456/1-1). T.J.S. is supported by the Deutsche Forschungsgemeinschaft (Jo 1324/1-1). H.Y.G. is supported by the National Research Foundation of Korea, Ministry of Science, ICT, and Future planning (2015R1D1A1A01056685) and faculty seed money from the Yonsei University College of Medicine (2015-32-0047). A.T.v.d.V. is supported by the DFG-fellowship (VE 196/1-1). We thank Yoko Chiba, Kumi Ito, Miyuki Tsuda, Mami Kikuchi, Makiko Nakagawa, Yoko Tateda and Kiyotaka Kuroda for their technical assistance. This work was supported by grants (17ek0109151h0003 and 17ek0109278h0001) from Japan Agency for Medical Research and Development (AMED) to S.K. We acknowledge the support of the Biomedical Research Unit of Tohoku University Hospital and the Biomedical Research Core and the Institute for Animal Experimentation of Tohoku University Graduate School of Medicine. N.A.S is supported by the Egyptian Group for Orphan Renal Diseases (EGORD). M.A.J. is supported by Department of Science and Technology, Govt. of India (DST-SERB). M.Z. was supported by the Deutsche Forschungsgemeinschaft (SFB423) Publisher Copyright: {\textcopyright} 2018 The Author(s).",

year = "2018",

month = dec,

day = "1",

doi = "10.1038/s41467-018-04193-w",

language = "English",

volume = "9",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

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, Stajić, 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, 'Mutations in six nephrosis genes delineate a pathogenic pathway amenable to treatment', Nature Communications, vol. 9, no. 1, 1960. https://doi.org/10.1038/s41467-018-04193-w

TY - JOUR

T1 - Mutations in six nephrosis genes delineate a pathogenic pathway amenable to treatment

AU - Ashraf, Shazia

AU - Kudo, Hiroki

AU - Rao, Jia

AU - Kikuchi, Atsuo

AU - Widmeier, Eugen

AU - Lawson, Jennifer A.

AU - Tan, Weizhen

AU - Hermle, Tobias

AU - Warejko, Jillian K.

AU - Shril, Shirlee

AU - Airik, Merlin

AU - Jobst-Schwan, Tilman

AU - Lovric, Svjetlana

AU - Braun, Daniela A.

AU - Gee, Heon Yung

AU - Schapiro, David

AU - Majmundar, Amar J.

AU - Sadowski, Carolin E.

AU - Pabst, Werner L.

AU - Daga, Ankana

AU - Van Der Ven, Amelie T.

AU - Schmidt, Johanna M.

AU - Low, Boon Chuan

AU - Gupta, Anjali Bansal

AU - Tripathi, Brajendra K.

AU - Wong, Jenny

AU - Campbell, Kirk

AU - Metcalfe, Kay

AU - Schanze, Denny

AU - Niihori, Tetsuya

AU - Kaito, Hiroshi

AU - Nozu, Kandai

AU - Tsukaguchi, Hiroyasu

AU - Tanaka, Ryojiro

AU - Hamahira, Kiyoshi

AU - Kobayashi, Yasuko

AU - Takizawa, Takumi

AU - Funayama, Ryo

AU - Nakayama, Keiko

AU - Aoki, Yoko

AU - Kumagai, Naonori

AU - Iijima, Kazumoto

AU - Fehrenbach, Henry

AU - Kari, Jameela A.

AU - El Desoky, Sherif

AU - Jalalah, Sawsan

AU - Bogdanovic, Radovan

AU - Stajić, Nataša

AU - Zappel, Hildegard

AU - Rakhmetova, Assel

AU - Wassmer, Sharon Rose

AU - Jungraithmayr, Therese

AU - Strehlau, Juergen

AU - Kumar, Aravind Selvin

AU - Bagga, Arvind

AU - Soliman, Neveen A.

AU - Mane, Shrikant M.

AU - Kaufman, Lewis

AU - Lowy, Douglas R.

AU - Jairajpuri, Mohamad A.

AU - Lifton, Richard P.

AU - Pei, York

AU - Zenker, Martin

AU - Kure, Shigeo

AU - Hildebrandt, Friedhelm

N1 - Funding Information: We are grateful to study individuals for their contribution. We acknowledge the Yale Center for Mendelian Genomics for whole exome sequencing. This research was supported by grants from the National Institutes of Health to F.H. (DK076683) and by the Howard Hughes Medical Institute to F.H. F.H. is the William E. Harmon Professor of Pediatrics. E.W. is supported by the German National Academy of Sciences Leopoldina (LPDS-2015-07). W.T. is supported by the ASN Foundation for Kidney Research. T.H. is supported by the DFG-fellowship (HE 7456/1-1). T.J.S. is supported by the Deutsche Forschungsgemeinschaft (Jo 1324/1-1). H.Y.G. is supported by the National Research Foundation of Korea, Ministry of Science, ICT, and Future planning (2015R1D1A1A01056685) and faculty seed money from the Yonsei University College of Medicine (2015-32-0047). A.T.v.d.V. is supported by the DFG-fellowship (VE 196/1-1). We thank Yoko Chiba, Kumi Ito, Miyuki Tsuda, Mami Kikuchi, Makiko Nakagawa, Yoko Tateda and Kiyotaka Kuroda for their technical assistance. This work was supported by grants (17ek0109151h0003 and 17ek0109278h0001) from Japan Agency for Medical Research and Development (AMED) to S.K. We acknowledge the support of the Biomedical Research Unit of Tohoku University Hospital and the Biomedical Research Core and the Institute for Animal Experimentation of Tohoku University Graduate School of Medicine. N.A.S is supported by the Egyptian Group for Orphan Renal Diseases (EGORD). M.A.J. is supported by Department of Science and Technology, Govt. of India (DST-SERB). M.Z. was supported by the Deutsche Forschungsgemeinschaft (SFB423). Funding Information: This research was supported by grants from the National Institutes of Health to F.H. (DK076683) and by the Howard Hughes Medical Institute to F.H. F.H. is the William E. Harmon Professor of Pediatrics. E.W. is supported by the German National Academy of Sciences Leopoldina (LPDS-2015-07). W.T. is supported by the ASN Foundation for Kidney Research. T.H. is supported by the DFG-fellowship (HE 7456/1-1). T.J.S. is supported by the Deutsche Forschungsgemeinschaft (Jo 1324/1-1). H.Y.G. is supported by the National Research Foundation of Korea, Ministry of Science, ICT, and Future planning (2015R1D1A1A01056685) and faculty seed money from the Yonsei University College of Medicine (2015-32-0047). A.T.v.d.V. is supported by the DFG-fellowship (VE 196/1-1). We thank Yoko Chiba, Kumi Ito, Miyuki Tsuda, Mami Kikuchi, Makiko Nakagawa, Yoko Tateda and Kiyotaka Kuroda for their technical assistance. This work was supported by grants (17ek0109151h0003 and 17ek0109278h0001) from Japan Agency for Medical Research and Development (AMED) to S.K. We acknowledge the support of the Biomedical Research Unit of Tohoku University Hospital and the Biomedical Research Core and the Institute for Animal Experimentation of Tohoku University Graduate School of Medicine. N.A.S is supported by the Egyptian Group for Orphan Renal Diseases (EGORD). M.A.J. is supported by Department of Science and Technology, Govt. of India (DST-SERB). M.Z. was supported by the Deutsche Forschungsgemeinschaft (SFB423) Publisher Copyright: © 2018 The Author(s).

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85047275091&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85047275091&partnerID=8YFLogxK

U2 - 10.1038/s41467-018-04193-w

DO - 10.1038/s41467-018-04193-w

M3 - Article

C2 - 29773874

AN - SCOPUS:85047275091

SN - 2041-1723

VL - 9

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1960

ER -

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

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