Recessive Mutations in SYNPO2 as a Candidate of Monogenic Nephrotic Syndrome
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:...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-02-01
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| Series: | Kidney International Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2468024920317113 |
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Article |
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DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Youying Mao Ronen Schneider Peter F.M. van der Ven Marvin Assent Keerthika Lohanadan Verena Klämbt Florian Buerger Thomas M. Kitzler Konstantin Deutsch Makiko Nakayama Amar J. Majmundar Nina Mann Tobias Hermle Ana C. Onuchic-Whitford Wei Zhou Nandini Nagarajan Margam Roy Duncan Jonathan Marquez Mustafa Khokha Hanan M. Fathy Jameela A. Kari Sherif El Desoky Loai A. Eid Hazem Subhi Awad Muna Al-Saffar Shrikant Mane Richard P. Lifton Dieter O. Fürst Shirlee Shril Friedhelm Hildebrandt |
| spellingShingle |
Youying Mao Ronen Schneider Peter F.M. van der Ven Marvin Assent Keerthika Lohanadan Verena Klämbt Florian Buerger Thomas M. Kitzler Konstantin Deutsch Makiko Nakayama Amar J. Majmundar Nina Mann Tobias Hermle Ana C. Onuchic-Whitford Wei Zhou Nandini Nagarajan Margam Roy Duncan Jonathan Marquez Mustafa Khokha Hanan M. Fathy Jameela A. Kari Sherif El Desoky Loai A. Eid Hazem Subhi Awad Muna Al-Saffar Shrikant Mane Richard P. Lifton Dieter O. Fürst Shirlee Shril Friedhelm Hildebrandt Recessive Mutations in SYNPO2 as a Candidate of Monogenic Nephrotic Syndrome Kidney International Reports monogenic kidney disease nephrotic syndrome SYNPO2 |
| author_facet |
Youying Mao Ronen Schneider Peter F.M. van der Ven Marvin Assent Keerthika Lohanadan Verena Klämbt Florian Buerger Thomas M. Kitzler Konstantin Deutsch Makiko Nakayama Amar J. Majmundar Nina Mann Tobias Hermle Ana C. Onuchic-Whitford Wei Zhou Nandini Nagarajan Margam Roy Duncan Jonathan Marquez Mustafa Khokha Hanan M. Fathy Jameela A. Kari Sherif El Desoky Loai A. Eid Hazem Subhi Awad Muna Al-Saffar Shrikant Mane Richard P. Lifton Dieter O. Fürst Shirlee Shril Friedhelm Hildebrandt |
| author_sort |
Youying Mao |
| title |
Recessive Mutations in SYNPO2 as a Candidate of Monogenic Nephrotic Syndrome |
| title_short |
Recessive Mutations in SYNPO2 as a Candidate of Monogenic Nephrotic Syndrome |
| title_full |
Recessive Mutations in SYNPO2 as a Candidate of Monogenic Nephrotic Syndrome |
| title_fullStr |
Recessive Mutations in SYNPO2 as a Candidate of Monogenic Nephrotic Syndrome |
| title_full_unstemmed |
Recessive Mutations in SYNPO2 as a Candidate of Monogenic Nephrotic Syndrome |
| title_sort |
recessive mutations in synpo2 as a candidate of monogenic nephrotic syndrome |
| publisher |
Elsevier |
| series |
Kidney International Reports |
| issn |
2468-0249 |
| publishDate |
2021-02-01 |
| description |
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. |
| topic |
monogenic kidney disease nephrotic syndrome SYNPO2 |
| url |
http://www.sciencedirect.com/science/article/pii/S2468024920317113 |
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doaj-dd37eae7f792449e9379ede47e4cb65a2021-02-11T04:23:31ZengElsevierKidney International Reports2468-02492021-02-0162472483Recessive Mutations in SYNPO2 as a Candidate of Monogenic Nephrotic SyndromeYouying Mao0Ronen Schneider1Peter F.M. van der Ven2Marvin Assent3Keerthika Lohanadan4Verena Klämbt5Florian Buerger6Thomas M. Kitzler7Konstantin Deutsch8Makiko Nakayama9Amar J. Majmundar10Nina Mann11Tobias Hermle12Ana C. Onuchic-Whitford13Wei Zhou14Nandini Nagarajan Margam15Roy Duncan16Jonathan Marquez17Mustafa Khokha18Hanan M. Fathy19Jameela A. Kari20Sherif El Desoky21Loai A. Eid22Hazem Subhi Awad23Muna Al-Saffar24Shrikant Mane25Richard P. Lifton26Dieter O. Fürst27Shirlee Shril28Friedhelm Hildebrandt29Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Nephrology, Shanghai Children’s Medical Center, Shanhai Jiaotong University, Shanghai, ChinaDepartment of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USAInstitute for Cell Biology, Department of Molecular Cell Biology, University of Bonn, Bonn, GermanyInstitute for Cell Biology, Department of Molecular Cell Biology, University of Bonn, Bonn, GermanyInstitute for Cell Biology, Department of Molecular Cell Biology, University of Bonn, Bonn, GermanyDepartment of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USADepartment of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USADepartment of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USADepartment of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USADepartment of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USADepartment of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USADepartment of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USADepartment of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USADepartment of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA; Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USADepartment of Nephrology, Shanghai Children’s Medical Center, Shanhai Jiaotong University, Shanghai, ChinaDepartment of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, CanadaDepartment of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, CanadaDepartment of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USADepartment of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USADepartment of Pediatrics, Alexandria Faculty of medicine, Alexandria University, Alexandria, EgyptDepartment of Pediatrics, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia; Pediatric Nephrology Center of Excellence, King Abdulaziz University, Jeddah, Kingdom of Saudi ArabiaDepartment of Pediatrics, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia; Pediatric Nephrology Center of Excellence, King Abdulaziz University, Jeddah, Kingdom of Saudi ArabiaPediatric Nephrology Department, Dubai Kidney Center of Excellence, Dubai Hospital, Dubai, United Arab EmiratesPediatric Nephrology Department, Dubai Kidney Center of Excellence, Dubai Hospital, Dubai, United Arab EmiratesDepartment of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA; United Arab Emirates University, Abu Dhabi, United Arab EmiratesDepartment of Genetics, Yale University School of Medicine, New Haven, Connecticut, USADepartment of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA; Howard Hughes Medical Institute, Chevy Chase, Maryland, USAInstitute for Cell Biology, Department of Molecular Cell Biology, University of Bonn, Bonn, GermanyDepartment of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USADepartment of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA; Correspondence: Friedhelm Hildebrandt, Boston Children’s Hospital, Enders 561, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.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.http://www.sciencedirect.com/science/article/pii/S2468024920317113monogenic kidney diseasenephrotic syndromeSYNPO2 |