DAAM2 Variants Cause Nephrotic Syndrome via Actin Dysregulation

Ronen Schneider; Konstantin Deutsch; Gregory J Hoeprich; Jonathan Marquez; Tobias Hermle; Daniela A Braun; Steve Seltzsam; Thomas M Kitzler; Youying Mao; Florian Buerger; Amar J Majmundar; Ana C Onuchic-Whitford; Caroline M Kolvenbach; Luca Schierbaum; Sophia Schneider; Abdul A Halawi; Makiko Nakayama; Nina Mann; Dervla M Connaughton; Verena Klämbt; Matias Wagner; Korbinian M Riedhammer; Lutz Renders; Yoshichika Katsura; Dean Thumkeo; Neveen A Soliman; Shrikant Mane; Richard P Lifton; Shirlee Shril; Mustafa K Khokha; Julia Hoefele; Bruce L Goode; Friedhelm Hildebrandt

doi:10.1016/j.ajhg.2020.11.008

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DAAM2 Variants Cause Nephrotic Syndrome via Actin Dysregulation

Journal article

Peer reviewed

DAAM2 Variants Cause Nephrotic Syndrome via Actin Dysregulation

Ronen Schneider, Konstantin Deutsch, Gregory J Hoeprich, Jonathan Marquez, Tobias Hermle, Daniela A Braun, Steve Seltzsam, Thomas M Kitzler, Youying Mao, Florian Buerger, …

American journal of human genetics, Vol.107(6), pp.1113-1128

12/03/2020

DOI: https://doi.org/10.1016/j.ajhg.2020.11.008

PMID: 33232676

Abstract

actin cytoskeleton

podocytopathy

steroid-resistant nephrotic syndrome

DAAM2

formins

monogenic kidney diseases

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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Title: DAAM2 Variants Cause Nephrotic Syndrome via Actin Dysregulation
Creators: Ronen Schneider - Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Konstantin Deutsch - Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Gregory J Hoeprich - Department of Biology, Brandeis University, Waltham, MA 02454, USA
Jonathan Marquez - Pediatric Genomics Discovery Program, Department of Pediatrics and Genetics, Yale University School of Medicine, New Haven, CT 06520, USA
Tobias Hermle - Renal Division, Department of Medicine, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg 79106, Germany
Daniela A Braun - Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Steve Seltzsam - Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Thomas M Kitzler - Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Youying Mao - Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Florian Buerger - Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Amar J Majmundar - Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Ana C Onuchic-Whitford - Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Caroline M Kolvenbach - Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Luca Schierbaum - Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Sophia Schneider - Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Abdul A Halawi - Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Makiko Nakayama - Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Nina Mann - Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Dervla M Connaughton - Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Verena Klämbt - Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Matias Wagner - Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich 81675, Germany
Korbinian M Riedhammer - Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich 81675, Germany
Lutz Renders - Department of Nephrology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich 81675, Germany
Yoshichika Katsura - Department of Drug Discovery Medicine, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan
Dean Thumkeo - Department of Drug Discovery Medicine, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan
Neveen A Soliman - Department of Pediatrics, Center of Pediatric Nephrology & Transplantation, Kasr Al Ainy School of Medicine, Cairo University, Cairo 11562, Egypt
Shrikant Mane - Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA
Richard P Lifton - Laboratory of Human Genetics and Genomics, the Rockefeller University, New York, NY 10065-6399, USA
Shirlee Shril - Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Mustafa K Khokha - Pediatric Genomics Discovery Program, Department of Pediatrics and Genetics, Yale University School of Medicine, New Haven, CT 06520, USA
Julia Hoefele - Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich 81675, Germany
Bruce L Goode - Department of Biology, Brandeis University, Waltham, MA 02454, USA
Friedhelm Hildebrandt - Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Publication Details: American journal of human genetics, Vol.107(6), pp.1113-1128
Publisher: Elsevier Inc
Identifiers: 9923979692701921
Academic Unit: Department of Biology; Rosenstiel Basic Medical Sciences Research Center
Language: English
Resource Type: Journal article

DAAM2 Variants Cause Nephrotic Syndrome via Actin Dysregulation

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