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Abstract: FR-PO1008

Mutations in 4 Diaphanous Related Formins as Novel Causes of Nephrotic Syndrome

Session Information

Category: Genetic Diseases of the Kidney

  • 1002 Genetic Diseases of the Kidney: Non-Cystic


  • Schneider, Ronen, Boston Children's Hospital, Boston, Massachusetts, United States
  • Ashraf, Shazia, Boston Childrens Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Klambt, Verena, Boston Children"s Hospital, Boston , Massachusetts, United States
  • Higgs, Henry N., Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States
  • Padilla lopez, Sergio, Phoenix Children''s Hospital, Phoenix, Arizona, United States
  • Kruer, Michael C., Phoenix Children?s Hospital, Phoenix, Arizona, United States
  • Braun, Daniela A., Boston Children's Hospital, HMS, Boston, Massachusetts, United States
  • Shril, Shirlee, Boston Childrens Hospital, Boston, Massachusetts, United States
  • Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States

Nephrotic Syndrome (NS) is the second most frequent cause of end-stage renal disease in the first 3 decades of life. Identification of >55 monogenic genes that cause NS if mutated (Vivante et al, Nat Rev Nephrol, 12:133, 2016), has rendered first insights into disease mechanisms of NS. Diaphanous Related Formins (DRF) regulate actin polymerization and bundling, and have a role in directing microtubules, filopodia and lamelipodia formation. Mutations in the DID domain of the Formin gene, INF2, have been shown to cause NS (Brown, Nat Gen, 42:72, 2010).


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


In 5 unrelated patients with early onset NS, we discovered recessive mutations in the following 4 DRF encoding genes: A homozygous mutation in DIAPH1 (individual B1678, p.Gln1098Leu). Gln1098 is part of the DIAPH1 actin nucleating domain, FH2. A hemizygous mutation In DIAPH2 (B2506, p.Arg1075Trp). Arg1075 is part of the basic region (‘RRKR’ sequence) of the DAD domain and is critical for auto-inhibition by binding to the DID domain. From the crystal structure of mDia1 we predict that the mutation would interrupt the DID-DAD interaction. In DIAPH3 we found mutations in two individuals with NS (A1938 p.Thr431Ala, homozygous, and F983 p.Asn346Ser; p.Arg28His compound het.). Thr431 is located in a loop between alpha helix 1 and alpha helix 2 of the predicted dimerization domain. In the crystal structure, Asn346 is in the DID domain and within the DAD-binding site, thus the Asn346Ser substitution is predicted to alter DID-DAD binding.
Furthermore, we found a mutation in DAAM2 (individual B1068, Ala335Gln, homozygous). Ala335 is located in the DID domain of DAAM2. All mutations are deemed disease causing by SIFT, MutTaster and PolyPhen2 prediction programs. All variants are absent hemizygously or homozygously from the gnomAD database.


We here discovered mutations in the DRF encoding genesDIAPH1,2,3 and DAAM2 as 4 potential novel monogenic causes of NS. Crystal structure analysis predicts disruption of the interacting domains DIA- DAD and of the interaction of FH2 with actin as the underlying mechanisms.


  • Other NIH Support