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Tytuł:
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Recessive Mutations in SYNPO2 as a Candidate of Monogenic Nephrotic Syndrome.
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Autorzy:
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Mao Y; Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.; Department of Nephrology, Shanghai Children's Medical Center, Shanhai Jiaotong University, Shanghai, China.
Schneider R; Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
van der Ven PFM; Institute for Cell Biology, Department of Molecular Cell Biology, University of Bonn, Bonn, Germany.
Assent M; Institute for Cell Biology, Department of Molecular Cell Biology, University of Bonn, Bonn, Germany.
Lohanadan K; Institute for Cell Biology, Department of Molecular Cell Biology, University of Bonn, Bonn, Germany.
Klämbt V; Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Buerger F; Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Kitzler TM; Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Deutsch K; Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Nakayama M; Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Majmundar AJ; Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Mann N; Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Hermle T; Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Onuchic-Whitford AC; Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.; Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Zhou W; Department of Nephrology, Shanghai Children's Medical Center, Shanhai Jiaotong University, Shanghai, China.
Margam NN; Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.
Duncan R; Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.
Marquez J; Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA.
Khokha M; Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA.
Fathy HM; Department of Pediatrics, Alexandria Faculty of medicine, Alexandria University, Alexandria, Egypt.
Kari JA; Department of Pediatrics, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.; Pediatric Nephrology Center of Excellence, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
El Desoky S; Department of Pediatrics, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.; Pediatric Nephrology Center of Excellence, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
Eid LA; Pediatric Nephrology Department, Dubai Kidney Center of Excellence, Dubai Hospital, Dubai, United Arab Emirates.
Awad HS; Pediatric Nephrology Department, Dubai Kidney Center of Excellence, Dubai Hospital, Dubai, United Arab Emirates.
Al-Saffar M; Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.; United Arab Emirates University, Abu Dhabi, United Arab Emirates.
Mane S; Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.
Lifton RP; Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.; Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
Fürst DO; Institute for Cell Biology, Department of Molecular Cell Biology, University of Bonn, Bonn, Germany.
Shril S; Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Hildebrandt F; Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
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Źródło:
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Kidney international reports [Kidney Int Rep] 2020 Nov 10; Vol. 6 (2), pp. 472-483. Date of Electronic Publication: 2020 Nov 10 (Print Publication: 2021).
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Typ publikacji:
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Journal Article
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Język:
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English
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Imprint Name(s):
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Original Publication: [Philadelphia] : Elsevier, [2016]-
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References:
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Grant Information:
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UL1 TR001863 United States TR NCATS NIH HHS; P30 DK079310 United States DK NIDDK NIH HHS; R01 DK076683 United States DK NIDDK NIH HHS; T32 DK007726 United States DK NIDDK NIH HHS; F32 DK122766 United States DK NIDDK NIH HHS
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Contributed Indexing:
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Keywords: SYNPO2; monogenic kidney disease; nephrotic syndrome
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Entry Date(s):
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Date Created: 20210222 Latest Revision: 20220420
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Update Code:
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20240105
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PubMed Central ID:
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PMC7879128
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DOI:
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10.1016/j.ekir.2020.10.040
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PMID:
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33615072
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Introduction: Most of the approximately 60 genes that if mutated cause steroid-resistant nephrotic syndrome (SRNS) are highly expressed in the glomerular podocyte, rendering SRNS a "podocytopathy."
Methods: We performed whole-exome sequencing (WES) in 1200 nephrotic syndrome (NS) patients.
Results: We discovered homozygous truncating and homozygous missense mutation in SYNPO2 (synaptopodin-2) (p.Lys1124∗ and p.Ala1134Thr) in 2 patients with childhood-onset NS. We found SYNPO2 expression in both podocytes and mesangial cells; however, notably, immunofluorescence staining of adult human and rat kidney cryosections indicated that SYNPO2 is localized mainly in mesangial cells. Subcellular localization studies reveal that in these cells SYNPO2 partially co-localizes with α-actinin and filamin A-containing F-actin filaments. Upon transfection in mesangial cells or podocytes, EGFP-SYNPO2 co-localized with α-actinin-4, which gene is mutated in autosomal dominant SRNS in humans. SYNPO2 overexpression increases mesangial cell migration rate (MMR), whereas shRNA knockdown reduces MMR. Decreased MMR was rescued by transfection of wild-type mouse Synpo2 cDNA but only partially by cDNA representing mutations from the NS patients. The increased mesangial cell migration rate (MMR) by SYNPO2 overexpression was inhibited by ARP complex inhibitor CK666. SYNPO2 shRNA knockdown in podocytes decreased active Rac1, which was rescued by transfection of wild-type SYNPO2 cDNA but not by cDNA representing any of the 2 mutant variants.
Conclusion: We show that SYNPO2 variants may lead to Rac1-ARP3 dysregulation, and may play a role in the pathogenesis of nephrotic syndrome.
(© 2020 International Society of Nephrology. Published by Elsevier Inc.)
