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

Research output: Contribution to journalArticle

19 Citations (Scopus)

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 languageEnglish
Article number1960
JournalNature communications
Volume9
Issue number1
DOIs
Publication statusPublished - 2018 Dec 1

Fingerprint

Nephrosis
Monomeric GTP-Binding Proteins
mutations
genes
Genes
Guanine Nucleotide Exchange Factors
Nephrotic Syndrome
Mutation
Dexamethasone
Chemical activation
Steroids
Therapeutics
kidney diseases
knockout mice
steroids
Proteins
phenotype
guanines
nucleotides
Podocytes

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

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), [1960]. https://doi.org/10.1038/s41467-018-04193-w
Ashraf, Shazia ; Kudo, Hiroki ; Rao, Jia ; Kikuchi, Atsuo ; Widmeier, Eugen ; Lawson, Jennifer A. ; Tan, Weizhen ; Hermle, Tobias ; Warejko, Jillian K. ; Shril, Shirlee ; Airik, Merlin ; Jobst-Schwan, Tilman ; Lovric, Svjetlana ; Braun, Daniela A. ; Gee, Heon Yung ; Schapiro, David ; Majmundar, Amar J. ; Sadowski, Carolin E. ; Pabst, Werner L. ; Daga, Ankana ; Van Der Ven, Amelie T. ; Schmidt, Johanna M. ; Low, Boon Chuan ; Gupta, Anjali Bansal ; Tripathi, Brajendra K. ; Wong, Jenny ; Campbell, Kirk ; Metcalfe, Kay ; Schanze, Denny ; Niihori, Tetsuya ; Kaito, Hiroshi ; Nozu, Kandai ; Tsukaguchi, Hiroyasu ; Tanaka, Ryojiro ; Hamahira, Kiyoshi ; Kobayashi, Yasuko ; Takizawa, Takumi ; Funayama, Ryo ; Nakayama, Keiko ; Aoki, Yoko ; Kumagai, Naonori ; Iijima, Kazumoto ; Fehrenbach, Henry ; Kari, Jameela A. ; El Desoky, Sherif ; Jalalah, Sawsan ; Bogdanovic, Radovan ; Stajić, Nataša ; Zappel, Hildegard ; Rakhmetova, Assel ; Wassmer, Sharon Rose ; Jungraithmayr, Therese ; Strehlau, Juergen ; Kumar, Aravind Selvin ; Bagga, Arvind ; Soliman, Neveen A. ; Mane, Shrikant M. ; Kaufman, Lewis ; Lowy, Douglas R. ; Jairajpuri, Mohamad A. ; Lifton, Richard P. ; Pei, York ; Zenker, Martin ; Kure, Shigeo ; Hildebrandt, Friedhelm. / Mutations in six nephrosis genes delineate a pathogenic pathway amenable to treatment. In: Nature communications. 2018 ; Vol. 9, No. 1.
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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.",
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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

Mutations in six nephrosis genes delineate a pathogenic pathway amenable to treatment. / Ashraf, Shazia; Kudo, Hiroki; Rao, Jia; Kikuchi, Atsuo; Widmeier, Eugen; Lawson, Jennifer A.; Tan, Weizhen; Hermle, Tobias; Warejko, Jillian K.; Shril, Shirlee; Airik, Merlin; Jobst-Schwan, Tilman; Lovric, Svjetlana; Braun, Daniela A.; Gee, Heon Yung; Schapiro, David; Majmundar, Amar J.; Sadowski, Carolin E.; Pabst, Werner L.; Daga, Ankana; Van Der Ven, Amelie T.; Schmidt, Johanna M.; Low, Boon Chuan; Gupta, Anjali Bansal; Tripathi, Brajendra K.; Wong, Jenny; Campbell, Kirk; Metcalfe, Kay; Schanze, Denny; Niihori, Tetsuya; Kaito, Hiroshi; Nozu, Kandai; Tsukaguchi, Hiroyasu; Tanaka, Ryojiro; Hamahira, Kiyoshi; Kobayashi, Yasuko; Takizawa, Takumi; Funayama, Ryo; Nakayama, Keiko; Aoki, Yoko; Kumagai, Naonori; Iijima, Kazumoto; Fehrenbach, Henry; Kari, Jameela A.; El Desoky, Sherif; Jalalah, Sawsan; Bogdanovic, Radovan; Stajić, Nataša; Zappel, Hildegard; Rakhmetova, Assel; Wassmer, Sharon Rose; Jungraithmayr, Therese; Strehlau, Juergen; Kumar, Aravind Selvin; Bagga, Arvind; Soliman, Neveen A.; Mane, Shrikant M.; Kaufman, Lewis; Lowy, Douglas R.; Jairajpuri, Mohamad A.; Lifton, Richard P.; Pei, York; Zenker, Martin; Kure, Shigeo; Hildebrandt, Friedhelm.

In: Nature communications, Vol. 9, No. 1, 1960, 01.12.2018.

Research output: Contribution to journalArticle

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

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.

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