DAAM2 Variants Cause Nephrotic Syndrome via Actin Dysregulation
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DAAM2 Variants Cause Nephrotic Syndrome via Actin Dysregulation. / Schneider, Ronen; Deutsch, Konstantin; Hoeprich, Gregory J; Marquez, Jonathan; Hermle, Tobias; Braun, Daniela A; Seltzsam, Steve; Kitzler, Thomas M; Mao, Youying; Buerger, Florian; Majmundar, Amar J; Onuchic-Whitford, Ana C; Kolvenbach, Caroline M; Schierbaum, Luca; Schneider, Sophia; Halawi, Abdul A; Nakayama, Makiko; Mann, Nina; Connaughton, Dervla M; Klämbt, Verena; Wagner, Matias; Riedhammer, Korbinian M; Renders, Lutz; Katsura, Yoshichika; Thumkeo, Dean; Soliman, Neveen A; Mane, Shrikant; Lifton, Richard P; Shril, Shirlee; Khokha, Mustafa K; Hoefele, Julia; Goode, Bruce L; Hildebrandt, Friedhelm.
in: AM J HUM GENET, Jahrgang 107, Nr. 6, 03.12.2020, S. 1113-1128.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - DAAM2 Variants Cause Nephrotic Syndrome via Actin Dysregulation
AU - Schneider, Ronen
AU - Deutsch, Konstantin
AU - Hoeprich, Gregory J
AU - Marquez, Jonathan
AU - Hermle, Tobias
AU - Braun, Daniela A
AU - Seltzsam, Steve
AU - Kitzler, Thomas M
AU - Mao, Youying
AU - Buerger, Florian
AU - Majmundar, Amar J
AU - Onuchic-Whitford, Ana C
AU - Kolvenbach, Caroline M
AU - Schierbaum, Luca
AU - Schneider, Sophia
AU - Halawi, Abdul A
AU - Nakayama, Makiko
AU - Mann, Nina
AU - Connaughton, Dervla M
AU - Klämbt, Verena
AU - Wagner, Matias
AU - Riedhammer, Korbinian M
AU - Renders, Lutz
AU - Katsura, Yoshichika
AU - Thumkeo, Dean
AU - Soliman, Neveen A
AU - Mane, Shrikant
AU - Lifton, Richard P
AU - Shril, Shirlee
AU - Khokha, Mustafa K
AU - Hoefele, Julia
AU - Goode, Bruce L
AU - Hildebrandt, Friedhelm
N1 - Copyright © 2020 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
PY - 2020/12/3
Y1 - 2020/12/3
N2 - 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.
AB - 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.
KW - Actins/metabolism
KW - Alleles
KW - Animals
KW - Animals, Genetically Modified
KW - Cell Movement/genetics
KW - Cytoplasm/metabolism
KW - Formins/metabolism
KW - Genetic Variation
KW - Humans
KW - Kidney/metabolism
KW - Kidney Glomerulus/metabolism
KW - Microfilament Proteins/genetics
KW - Mutation, Missense
KW - Nephrotic Syndrome/genetics
KW - Podocytes/metabolism
KW - Pseudopodia/metabolism
KW - RNA, Small Interfering/metabolism
KW - Exome Sequencing
KW - Xenopus
KW - rho GTP-Binding Proteins/genetics
U2 - 10.1016/j.ajhg.2020.11.008
DO - 10.1016/j.ajhg.2020.11.008
M3 - SCORING: Journal article
C2 - 33232676
VL - 107
SP - 1113
EP - 1128
JO - AM J HUM GENET
JF - AM J HUM GENET
SN - 0002-9297
IS - 6
ER -