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

doi:10.1038/s41467-019-10087-2

GSTDTAP > 资源环境科学

DOI	10.1038/s41467-019-10087-2
	Mutations in six nephrosis genes delineate a pathogenic pathway amenable to treatment
	Ashraf, Shazia 1,2; Kudo, Hiroki 3; Rao, Jia 1; Kikuchi, Atsuo 3; Widmeier, Eugen 1; Lawson, Jennifer A.1; Tan, Weizhen 1; Hermle, Tobias 1; Warejko, Jillian K.1; Shril, Shirlee 1; Airik, Merlin 1; Jobst-Schwan, Tilman 1; Lovric, Svjetlana 1; Braun, Daniela A.1; Gee, Heon Yung 1,4; Schapiro, David 1; Majmundar, Amar J.1; Sadowski, Carolin E.1; Pabst, Werner L.1; Daga, Ankana 1; van der Ven, Amelie T.1; Schmidt, Johanna M.1; Low, Boon Chuan 5,6; Gupta, Anjali Bansal 6; Tripathi, Brajendra K.7; Wong, Jenny 8; Campbell, Kirk 8; Metcalfe, Kay 9; Schanze, Denny 10; Niihori, Tetsuya 11; Kaito, Hiroshi 12; Nozu, Kandai 12; Tsukaguchi, Hiroyasu 13; Tanaka, Ryojiro 14; Hamahira, Kiyoshi 15; Kobayashi, Yasuko 16,17; Takizawa, Takumi 16; Funayama, Ryo 18; Nakayama, Keiko 18; Aoki, Yoko 11; Kumagai, Naonori 3; Iijima, Kazumoto 12; Fehrenbach, Henry 19; Kari, Jameela A.20,21; El Desoky, Sherif 20,21; Jalalah, Sawsan 22; Bogdanovic, Radovan 23; Stajic, Natasa 23; Zappel, Hildegard 24; Rakhmetova, Assel 25; Wassmer, Sharon-Rose 26; Jungraithmayr, Therese 27; Strehlau, Juergen 28; Kumar, Aravind Selvin 29,30; Bagga, Arvind 31; Soliman, Neveen A.32; Mane, Shrikant M.33; Kaufman, Lewis 8; Lowy, Douglas R.7; Jairajpuri, Mohamad A.2; Lifton, Richard P.33,34; Pei, York 35,36; Zenker, Martin 10; Kure, Shigeo 3; Hildebrandt, Friedhelm 1
	2019-05-21
发表期刊	NATURE COMMUNICATIONS
ISSN	2041-1723
出版年	2018
卷号	9
文章类型	Article
语种	英语
国家	USA; India; Japan; South Korea; Singapore; England; Germany; Saudi Arabia; Serbia; Kazakhstan; Switzerland; Austria; Egypt; Canada
英文摘要	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.
领域	资源环境
收录类别	SCI-E
WOS记录号	WOS:000432343700002
WOS关键词	MULTIPOINT LINKAGE ANALYSIS ; TUMOR-SUPPRESSOR DLC1 ; SCAFFOLD PROTEIN ; RHO GTPASES ; ACTIN ; CAVEOLIN-1 ; CILIOPATHY ; EXPRESSION ; MIGRATION ; MAGI-2
WOS类目	Multidisciplinary Sciences
WOS研究方向	Science & Technology - Other Topics
URL	查看原文
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/204379
专题	资源环境科学
作者单位	1.Harvard Med Sch, Boston Childrens Hosp, Dept Med, Boston, MA USA; 2.Jamia Millia Islamia, Dept Biosci, New Delhi, India; 3.Tohoku Univ, Dept Pediat, Sch Med, Aoba Ku, 1-1 Seiryo Machi, Sendai, Miyagi 9808574, Japan; 4.Yonsei Univ, Dept Pharmacol, Brain Korea PLUS Project Med Sci 21, Coll Med, Seoul 03722, South Korea; 5.Natl Univ Singapore, Dept Biol Sci, Singapore, Singapore; 6.Natl Univ Singapore, Mechanobiol Inst, Singapore, Singapore; 7.NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA; 8.Icahn Sch Med Mt Sinai, Div Nephrol, New York, NY 10029 USA; 9.Cent Manchester Univ Hosp NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, Manchester Ctr Genom Med, St Marys Hosp, Manchester, Lancs, England; 10.Univ Hosp Magdeburg, Inst Human Genet, Magdeburg, Germany; 11.Tohoku Univ, Sch Med, Dept Med Genet, Aoba Ku, 1-1 Seiryo Machi, Sendai, Miyagi 9808574, Japan; 12.Kobe Univ, Dept Pediat, Grad Sch Med, Chuo Ku, 7-5-2 Kusunoki Cho, Kobe, Hyogo 6500017, Japan; 13.Kansai Med Univ, Dept Internal Med 2, 2-3-1 Shin Machi, Hirakata, Osaka 5731191, Japan; 14.Hyogo Prefectural Kobe Childrens Hosp, Dept Nephrol, Chuo Ku, 1-6-7 Minatojima Minamimachi, Kobe, Hyogo 6500047, Japan; 15.Himeji Red Cross Hosp, Dept Pediat, 1-12-1 Shimoteno, Himeji, Hyogo 6708540, Japan; 16.Gunma Univ, Grad Sch Med, Dept Pediat, 3-39-22 Showa Machi, Maebashi, Gunma 3718511, Japan; 17.Univ Bristol, Sch Clin Sci, Acad Renal Unit, Dorothy Hodgkin Bldg,Whitson St, Bristol BS1 3NY, Avon, England; 18.Tohoku Univ, Grad Sch Med, United Ctr Adv Res & Translat Med, Div Cell Proliferat, Sendai, Miyagi 9808575, Japan; 19.Childrens Hosp, Dept Pediat Nephrol, Memmingen, Germany; 20.King Abdulaziz Univ, Pediat Nephrol Ctr Excellence, Jeddah, Saudi Arabia; 21.King Abdulaziz Univ, Pediat Dept, Jeddah, Saudi Arabia; 22.King Abdulaziz Univ, Pathol Dept, Jeddah, Saudi Arabia; 23.Univ Belgrade, Fac Med, Dept Nephrol, Inst Mother & Child Hlth Care Serbia Dr Vukan Cup, Belgrade 11000, Serbia; 24.Univ Gottingen, Dept Paediat 2, Gottingen, Germany; 25.Asfendiyarov Kazakh Natl Med Univ, Dept Nephrol, Alma Ata, Kazakhstan; 26.Luzerner Kantonsspital, Dept Nephrol, Luzern, Switzerland; 27.Univ Med Ctr Innsbruck, Dept Pediat, Innsbruck, Austria; 28.Hannover Med Sch, Dept Pediat Nephrol, Hannover, Germany; 29.TN Dr MGR Med Univ, Inst Child Hlth, Dept Pediat Nephrol & Med Genet, Madras, Tamil Nadu, India; 30.TN Dr MGR Med Univ, Hosp Children, Madras, Tamil Nadu, India; 31.All India Inst Med Sci, Dept Pediat, Div Pediat Nephrol, New Delhi, India; 32.Cairo Univ, Kasr Al Ainy Sch Med, Ctr Pediat Nephrol & Transplantat, Dept Pediat, Cairo, Egypt; 33.Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA; 34.Rockefeller Univ, Lab Human Genet & Genom, New York, NY 10065 USA; 35.Univ Hlth Network, Div Nephrol, Toronto, ON, Canada; 36.Univ Toronto, Toronto, ON, Canada
推荐引用方式 GB/T 7714	Ashraf, Shazia,Kudo, Hiroki,Rao, Jia,et al. Mutations in six nephrosis genes delineate a pathogenic pathway amenable to treatment[J]. NATURE COMMUNICATIONS,2019,9.
APA	Ashraf, Shazia.,Kudo, Hiroki.,Rao, Jia.,Kikuchi, Atsuo.,Widmeier, Eugen.,...&Hildebrandt, Friedhelm.(2019).Mutations in six nephrosis genes delineate a pathogenic pathway amenable to treatment.NATURE COMMUNICATIONS,9.
MLA	Ashraf, Shazia,et al."Mutations in six nephrosis genes delineate a pathogenic pathway amenable to treatment".NATURE COMMUNICATIONS 9(2019).