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Nat Commun. 2018 May 17;9(1):1960. doi: 10.1038/s41467-018-04193-w.

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

Author information

1
Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
2
Department of Biosciences, Jamia Millia Islamia, New Delhi, India.
3
Department of Pediatrics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.
4
Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, 03722, Korea.
5
Department of Biological Sciences, National University of Singapore, Singapore, Singapore.
6
Mechanobiology Institute, National University of Singapore, Singapore, Singapore.
7
Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
8
Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
9
Manchester Centre for Genomic Medicine, St Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
10
Institute of Human Genetics, University Hospital Magdeburg, Magdeburg, Germany.
11
Department of Medical Genetics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.
12
Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
13
2nd Department of Internal Medicine, Kansai Medical University, 2-3-1 Shin-machi, Hirakata-shi, Osaka, 573-1191, Japan.
14
Department of Nephrology, Hyogo Prefectural Kobe Children's Hospital, 1-6-7 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan.
15
Department of Pediatrics, Himeji Red Cross Hospital, 1-12-1 Shimoteno, Himeji, Hyogo, 670-8540, Japan.
16
Department of Pediatrics, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan.
17
Academic Renal Unit, School of Clinical Science, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol, BS1 3NY, United Kingdom.
18
Division of Cell Proliferation, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, 980-8575, Japan.
19
Department of Pediatric Nephrology, Children's Hospital, Memmingen, Germany.
20
Pediatric Nephrology Center of Excellence and Pediatric Department, King Abdulaziz University, Jeddah, Saudi Arabia.
21
Pathology Department, King Abdulaziz University, Jeddah, Saudi Arabia.
22
Institute for Mother and Child Health Care of Serbia "Dr Vukan Čupić", Department of Nephrology, University of Belgrade, Faculty of Medicine, Belgrade, 11000, Serbia.
23
Department for Paediatrics II, University of Göttingen, Göttingen, Germany.
24
Department of Nephrology, Asfendiyarov Kazakh National Medical University, Almaty, Kazakhstan.
25
Department of Nephrology, Luzerner Kantonsspital, Lucerne, Switzerland.
26
Department of Pediatrics, University Medical Center Innsbruck, Innsbruck, Austria.
27
Department of Pediatric Nephrology, Hannover Medical School, Hannover, Germany.
28
Department of Pediatric Nephrology and Medical Genetics, Institute of Child Health and Hospital for Children, TN Dr.M.G.R. Medical University, Chennai, India.
29
Division of Pediatric Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.
30
Department of Pediatrics, Center of Pediatric Nephrology & Transplantation, Kasr Al Ainy School of Medicine, Cairo University, Cairo, Egypt.
31
Department of Genetics, Yale University School of Medicine, New Haven, CT, 06510, USA.
32
Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, 10065, USA.
33
Division of Nephrology, University Health Network, and University of Toronto, Toronto, ON, Canada.
34
Department of Pediatrics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan. kure@med.tohoku.ac.jp.
35
Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. friedhelm.hildebrandt@childrens.harvard.edu.

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.

PMID:
29773874
PMCID:
PMC5958119
DOI:
10.1038/s41467-018-04193-w
[Indexed for MEDLINE]
Free PMC Article

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