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DOI 10.1038/s41467-018-04193-w

Медицинская библиотека · Nature communications · 2018

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

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Аннотация

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.

Для цитирования: 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.. Nature communications. 2018. DOI: 10.1038/s41467-018-04193-w.

Предметные рубрики MeSH

AdultAnimalsChildChild, PreschoolDNA Mutational AnalysisDisease Models, AnimalDrug ResistanceFemaleGene Knockdown TechniquesGlucocorticoidsHEK293 CellsHigh-Throughput Nucleotide SequencingHumansInfantMaleMiceMice, Inbred C57BLMice, KnockoutMiddle AgedMutationNephrotic SyndromePedigreePodocytesProtein Interaction MapsRNA, Small InterferingTreatment OutcomeExome SequencingrhoA GTP-Binding Protein
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