PortalPublikationenMutations in six nephrosis genes delineate a pathogenic path...

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

Standard

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: NAT COMMUN, Jahrgang 9, Nr. 1, 17.05.2018, S. 1960.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

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, S-R, 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', NAT COMMUN, Jg. 9, Nr. 1, S. 1960. https://doi.org/10.1038/s41467-018-04193-w

APA

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. NAT COMMUN, 9(1), 1960. https://doi.org/10.1038/s41467-018-04193-w

Vancouver

Ashraf S, Kudo H, Rao J, Kikuchi A, Widmeier E, Lawson JA et al. Mutations in six nephrosis genes delineate a pathogenic pathway amenable to treatment. NAT COMMUN. 2018 Mai 17;9(1):1960. https://doi.org/10.1038/s41467-018-04193-w

Bibtex

@article{5a66ca6a0b1f495997f8444bf9be4bca,
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.",
keywords = "Adult, Animals, Child, Child, Preschool, DNA Mutational Analysis, Disease Models, Animal, Drug Resistance/genetics, Female, Gene Knockdown Techniques, Glucocorticoids/pharmacology, HEK293 Cells, High-Throughput Nucleotide Sequencing, Humans, Infant, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Mutation, Nephrotic Syndrome/drug therapy, Pedigree, Podocytes, Protein Interaction Maps/genetics, RNA, Small Interfering/metabolism, Treatment Outcome, Whole Exome Sequencing, rhoA GTP-Binding Protein/genetics",
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 Sharon-Rose Wassmer 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",
year = "2018",
month = may,
day = "17",
doi = "10.1038/s41467-018-04193-w",
language = "English",
volume = "9",
pages = "1960",
journal = "NAT COMMUN",
issn = "2041-1723",
publisher = "NATURE PUBLISHING GROUP",
number = "1",

}

RIS

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 - 2018/5/17

Y1 - 2018/5/17

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.

KW - Adult

KW - Animals

KW - Child

KW - Child, Preschool

KW - DNA Mutational Analysis

KW - Disease Models, Animal

KW - Drug Resistance/genetics

KW - Female

KW - Gene Knockdown Techniques

KW - Glucocorticoids/pharmacology

KW - HEK293 Cells

KW - High-Throughput Nucleotide Sequencing

KW - Humans

KW - Infant

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Middle Aged

KW - Mutation

KW - Nephrotic Syndrome/drug therapy

KW - Pedigree

KW - Podocytes

KW - Protein Interaction Maps/genetics

KW - RNA, Small Interfering/metabolism

KW - Treatment Outcome

KW - Whole Exome Sequencing

KW - rhoA GTP-Binding Protein/genetics

U2 - 10.1038/s41467-018-04193-w

DO - 10.1038/s41467-018-04193-w

M3 - SCORING: Journal article

C2 - 29773874

VL - 9

SP - 1960

JO - NAT COMMUN

JF - NAT COMMUN

SN - 2041-1723

IS - 1

ER -