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Am J Hum Genet January 1, 2020; 107 (6): 1113-1128.

DAAM2 Variants Cause Nephrotic Syndrome via Actin Dysregulation.

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 .

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.

PubMed ID: 33232676
PMC ID: PMC7820625
Article link: Am J Hum Genet
Grant support: [+]

Species referenced: Xenopus
Genes referenced: cdc42 daam2 fmn1 rac1 rhoa

Disease Ontology terms: nephrotic syndrome [+]
References [+] :
A, Regulation of INF2-mediated actin polymerization through site-specific lysine acetylation of actin itself. 2020, Pubmed