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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, Vol. 107, No. 6, 03.12.2020, p. 1113-1128.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Schneider, R, Deutsch, K, Hoeprich, GJ, Marquez, J, Hermle, T, Braun, DA, Seltzsam, S, Kitzler, TM, Mao, Y, Buerger, F, Majmundar, AJ, Onuchic-Whitford, AC, Kolvenbach, CM, Schierbaum, L, Schneider, S, Halawi, AA, Nakayama, M, Mann, N, Connaughton, DM, Klämbt, V, Wagner, M, Riedhammer, KM, Renders, L, Katsura, Y, Thumkeo, D, Soliman, NA, Mane, S, Lifton, RP, Shril, S, Khokha, MK, Hoefele, J, Goode, BL & Hildebrandt, F 2020, 'DAAM2 Variants Cause Nephrotic Syndrome via Actin Dysregulation', AM J HUM GENET, vol. 107, no. 6, pp. 1113-1128. https://doi.org/10.1016/j.ajhg.2020.11.008

APA

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., ... Hildebrandt, F. (2020). DAAM2 Variants Cause Nephrotic Syndrome via Actin Dysregulation. AM J HUM GENET, 107(6), 1113-1128. https://doi.org/10.1016/j.ajhg.2020.11.008

Vancouver

Schneider R, Deutsch K, Hoeprich GJ, Marquez J, Hermle T, Braun DA et al. DAAM2 Variants Cause Nephrotic Syndrome via Actin Dysregulation. AM J HUM GENET. 2020 Dec 3;107(6):1113-1128. https://doi.org/10.1016/j.ajhg.2020.11.008

Bibtex

@article{18b2a0b695ba4409a18883ce5a068420,
title = "DAAM2 Variants Cause Nephrotic Syndrome via Actin Dysregulation",
abstract = "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.",
keywords = "Actins/metabolism, Alleles, Animals, Animals, Genetically Modified, Cell Movement/genetics, Cytoplasm/metabolism, Formins/metabolism, Genetic Variation, Humans, Kidney/metabolism, Kidney Glomerulus/metabolism, Microfilament Proteins/genetics, Mutation, Missense, Nephrotic Syndrome/genetics, Podocytes/metabolism, Pseudopodia/metabolism, RNA, Small Interfering/metabolism, Exome Sequencing, Xenopus, rho GTP-Binding Proteins/genetics",
author = "Ronen Schneider and Konstantin Deutsch and Hoeprich, {Gregory J} and Jonathan Marquez and Tobias Hermle and Braun, {Daniela A} and Steve Seltzsam and Kitzler, {Thomas M} and Youying Mao and Florian Buerger and Majmundar, {Amar J} and Onuchic-Whitford, {Ana C} and Kolvenbach, {Caroline M} and Luca Schierbaum and Sophia Schneider and Halawi, {Abdul A} and Makiko Nakayama and Nina Mann and Connaughton, {Dervla M} and Verena Kl{\"a}mbt and Matias Wagner and Riedhammer, {Korbinian M} and Lutz Renders and Yoshichika Katsura and Dean Thumkeo and Soliman, {Neveen A} and Shrikant Mane and Lifton, {Richard P} and Shirlee Shril and Khokha, {Mustafa K} and Julia Hoefele and Goode, {Bruce L} and Friedhelm Hildebrandt",
note = "Copyright {\textcopyright} 2020 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.",
year = "2020",
month = dec,
day = "3",
doi = "10.1016/j.ajhg.2020.11.008",
language = "English",
volume = "107",
pages = "1113--1128",
journal = "AM J HUM GENET",
issn = "0002-9297",
publisher = "Cell Press",
number = "6",

}

RIS

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 -