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Schneider, R.* ; Deutsch, K.* ; Hoeprich, G.J.* ; Marquez, J.* ; Hermle, T.* ; Braun, D.A.* ; Seltzsam, S.* ; Kitzler, T.M.* ; Mao, Y.* ; Buerger, F.* ; Majmundar, A.J.* ; Onuchic-Whitford, A.C.* ; Kolvenbach, C.M.* ; Schierbaum, L.* ; Schneider, S.* ; Halawi, A.A.* ; Nakayama, M.* ; Mann, N.* ; Connaughton, D.M.* ; Klämbt, V.* ; Wagner, M. ; Riedhammer, K.M.* ; Renders, L.* ; Katsura, Y.* ; Thumkeo, D.* ; Soliman, N.A.* ; Mane, S.* ; Lifton, R.P.* ; Shril, S.* ; Khokha, M.K.* ; Hoefele, J.* ; Goode, B.L.* ; Hildebrandt, F.*

DAAM2 variants cause nephrotic syndrome via actin dysregulation.

Am. J. Hum. Genet. 107, 1113-1128 (2020)
Publ. Version/Full Text Research data DOI
Open Access Green as soon as Postprint is submitted to ZB.
The discovery of >60 monogenic causes of nephrotic syndrome (NS) has revealed a central role for the actin regulators RhoA/Rac1/Cdc42 and their effectors, including the formin INF2. By whole-exome sequencing (WES), we here discovered bi-allelic variants in the formin DAAM2 in four unrelated families with steroid-resistant NS. We show that DAAM2 localizes to the cytoplasm in podocytes and in kidney sections. Further, the variants impair DAAM2-dependent actin remodeling processes: wild-type DAAM2 cDNA, but not cDNA representing missense variants found in individuals with NS, rescued reduced podocyte migration rate (PMR) and restored reduced filopodia formation in shRNA-induced DAAM2-knockdown podocytes. Filopodia restoration was also induced by the formin-activating molecule IMM-01. DAAM2 also co-localizes and co-immunoprecipitates with INF2, which is intriguing since variants in both formins cause NS. Using in vitro bulk and TIRF microscopy assays, we find that DAAM2 variants alter actin assembly activities of the formin. In a Xenopus daam2-CRISPR knockout model, we demonstrate actin dysregulation in vivo and glomerular maldevelopment that is rescued by WT-DAAM2 mRNA. We conclude that DAAM2 variants are a likely cause of monogenic human SRNS due to actin dysregulation in podocytes. Further, we provide evidence that DAAM2-associated SRNS may be amenable to treatment using actin regulating compounds.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Actin Cytoskeleton ; Daam2 ; Formins ; Monogenic Kidney Diseases ; Podocytopathy ; Steroid-resistant Nephrotic Syndrome
ISSN (print) / ISBN 0002-9297
e-ISSN 1537-6605
Quellenangaben Volume: 107, Issue: 6, Pages: 1113-1128 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place New York, NY
Reviewing status Peer reviewed
Grants GSP Coordinating Center
Canadian Society of Nephrology
KRESCENT Program, a national kidney research training partnership of the Kidney Foundation of Canada
Deutsche Forschungsgemeinschaft (DFG, German Research foundation)
Paul and Daisy Soros Fellowship for New Americans
Yale Predoctoral Program in Cellular and Molecular Biology
R35 award from the National Institutes of Health
National Institutes of Health
Canadian Institutes of Health Research
NIH Training Grant
MEXT of the Japanese Government
Deutsche Forschungsgemeinschaft
Amgen Irish Nephrology Society Specialist Registrar Bursary
International Pediatric Research Foundation Early Investigators' Exchange Program
Health Research Board, Ireland
NIH F32 Ruth L. Kirschstein Postdoctoral Individual National Research Service Award
American Society of Nephrology Lipps Research Program 2018 Polycystic Kidney Disease Foundation Jared J. Grantham Research Fellowship
2017 Post-doctoral Fellowship Grant from the Harvard Stem Cell Institute
National Human Genome Research Institute