Mutations in six nephrosis genes delineate a pathogenic pathway amenable to treatment
| Autor: | Yasuko Kobayashi, Heon Yung Gee, Juergen Strehlau, York Pei, Shigeo Kure, Therese Jungraithmayr, Kirk N. Campbell, Shirlee Shril, Assel Rakhmetova, Weizhen Tan, Henry Fehrenbach, Mohamad Aman Jairajpuri, Amelie T. van der Ven, Sharon Rose Wassmer, Aravind Selvin Kumar, Friedhelm Hildebrandt, Naonori Kumagai, Neveen A. Soliman, Tilman Jobst-Schwan, Shrikant M. Mane, Jennifer A. Lawson, Atsuo Kikuchi, Ankana Daga, Boon Chuan Low, Hildegard Zappel, Denny Schanze, Martin Zenker, Svjetlana Lovric, Sherif El Desoky, Natasa Stajic, Kandai Nozu, Lewis Kaufman, Jameela A. Kari, Hiroki Kudo, Carolin E. Sadowski, Hiroyasu Tsukaguchi, Jenny Wong, Takumi Takizawa, Jillian K. Warejko, Kazumoto Iijima, Kay Metcalfe, David Schapiro, Daniela A. Braun, Johanna Magdalena Schmidt, Tobias Hermle, Brajendra K. Tripathi, Hiroshi Kaito, Eugen Widmeier, Radovan Bogdanovic, Merlin Airik, Douglas R. Lowy, Keiko Nakayama, Werner L. Pabst, Ryo Funayama, Arvind Bagga, Amar J. Majmundar, Ryojiro Tanaka, Richard P. Lifton, Tetsuya Niihori, Jia Rao, Kiyoshi Hamahira, Sawsan M Jalalah, Yoko Aoki, Anjali Gupta, Shazia Ashraf |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Nephrotic Syndrome RHOA Chemistry(all) DNA Mutational Analysis Drug Resistance 030232 urology & nephrology General Physics and Astronomy medicine.disease_cause GTP Phosphohydrolases Mice 0302 clinical medicine Small GTPase Protein Interaction Maps RNA Small Interfering lcsh:Science Child Mice Knockout Mutation Gene knockdown Multidisciplinary biology Podocytes High-Throughput Nucleotide Sequencing Middle Aged Phenotype Pedigree 3. Good health Cell biology Treatment Outcome Child Preschool Gene Knockdown Techniques Knockout mouse Female Guanine nucleotide exchange factor Adult Science Nephrosis Physics and Astronomy(all) Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Exome Sequencing medicine Animals Humans Glucocorticoids Biochemistry Genetics and Molecular Biology(all) Infant General Chemistry medicine.disease Mice Inbred C57BL Disease Models Animal HEK293 Cells 030104 developmental biology biology.protein lcsh:Q rhoA GTP-Binding Protein |
| Zdroj: | Nature Communications, Vol 9, Iss 1, Pp 1-14 (2018) Nature Communications 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, Daga, A, Van Der Ven, A T, Schmidt, J M, Low, B C, Gupta, A B, Tripathi, B K, 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, J A, El Desoky, S, Jalalah, S, Bogdanovic, R, Stajić, N, Zappel, H, Rakhmetova, A, Wassmer, S R, Jungraithmayr, T, Strehlau, J, Kumar, A S, Bagga, A, Soliman, N A, Mane, S M, Kaufman, L, Lowy, D R, Jairajpuri, M A, Lifton, R P, 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 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, Daga, A, Van Der Ven, A T, Schmidt, J M, Low, B C, Gupta, A B, Tripathi, B K, 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, J A, El Desoky, S, Jalalah, S, Bogdanovic, R, Stajić, N, Zappel, H & Rakhmetova, A 2018, ' Mutations in six nephrosis genes delineate a pathogenic pathway amenable to treatment ', Nature Communications, vol. 9, 1960 . https://doi.org/10.1038/s41467-018-04193-w |
| ISSN: | 2041-1723 |
| Popis: | 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. Nephrotic syndrome is the second most common chronic kidney disease but there are no targeted treatment strategies available. Here the authors identify mutations of six genes codifying for proteins involved in cytoskeleton remodelling and modulation of small GTPases in 17 families with nephrotic syndrome. |
| Databáze: | OpenAIRE |
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