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Kidney Week

Abstract: FR-PO787

Mutations in the Diaphanous Related Formin DAAM2 as a Novel Cause of Nephrotic Syndrome

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Schneider, Ronen, Boston Children's Hospital, Boston, Massachusetts, United States
  • Deutsch, Konstantin, Boston Children's Hospital, Boston, Massachusetts, United States
  • Hoeprich, Gregory, Brandeis University, Waltham, Massachusetts, United States
  • Braun, Daniela A., University Hospital of Muenster, Muenster, NW, Germany
  • Kitzler, Thomas Michael, Boston Children's Hospital, Boston, Massachusetts, United States
  • Mao, Youying, Boston Children's Hospital, Boston, Massachusetts, United States
  • Majmundar, Amar J., Boston Children's Hospital, Boston, Massachusetts, United States
  • Buerger, Florian, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Wagner, Matias, Technical University of Munich, Munich, Germany
  • Riedhammer, Korbinian M., Technical University of Munich, Munich, Germany
  • Renders, Lutz, Technical University of Munich, Munich, Germany
  • Shril, Shirlee, Boston Children's Hospital, Boston, Massachusetts, United States
  • Hoefele, Julia, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany
  • Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States
Background

Steroid Resistant Nephrotic Syndrome (SRNS) is the second most frequent cause of end-stage renal disease in the first 3 decades of life. Identification of >55 monogenic causes of NS has rendered insights into disease mechanisms of NS (Nat Rev Nephrol. 12:133, 2016). Diaphanous related formins (DRF) regulate actin polymerization, filopodia and lamelipodia formation. The basal state interaction of the N-terminal DID domain with the C-terminal DAD domain is autoinhibitory and is relieved by conformational changes induced by GTPases. Accordingly, mutations in the DID domain of the formin gene, INF2, cause NS (Nat Gen 42:72, 2010).

Methods

To identify novel monogenic causes of NS we performed whole exome sequencing (WES) in a worldwide cohort of ~600 individuals with NS.

Results

In the three unrelated families (B1068, HN-F25, and HN-F627) with SRNS, we discovered three different homozygous mutations in the formin DAAM2: p.R335Q (located in the DID domain), p.S1027L (in the DAD domain), and p.R445* (terminating DAAM2 after the DID domain). All mutations are deemed disease causing by prediction programs and are absent homozygously and very rare heterozygously in the gnomAD database. We show that DAAM2 localizes to podocyte foot processes by immunofluorescence. In the podocyte migration rate assay (PMR), DAAM2 knockdown by shRNA reduced PMR. PMR was rescued by overexpressing WT-DAAM2 cDNA but not by the cDNA representing the human missense mutations. In podocytes, filopodia formation was induced by overexpressing GFP-WT-DAAM2 cDNA but not by the cDNA representing the human missense mutations. Applying the formin activating small molecule IMM-01 caused filopodia formation in shRNA DAAM2-k.d. podocytes in a dose-dependent manner, and overcame the filopodia formation defect of mutant cDNA overexpression.

Conclusion

We here discovered mutations in the formin DAAM2 as a novel monogenic cause of NS. We demonstrate that mutations of DAAM2 cause loss of filopodia formation and reduced PMR as intermediate phenotypes in NS, linking the pathomechanism to formin regulation. DAAM2 is likely a potential target for formin activating drugs.

Funding

  • NIDDK Support