ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling

J Clin Invest. 2013 Aug;123(8):3243-53. doi: 10.1172/JCI69134. Epub 2013 Jul 8.


Nephrotic syndrome (NS) is divided into steroid-sensitive (SSNS) and -resistant (SRNS) variants. SRNS causes end-stage kidney disease, which cannot be cured. While the disease mechanisms of NS are not well understood, genetic mapping studies suggest a multitude of unknown single-gene causes. We combined homozygosity mapping with whole-exome resequencing and identified an ARHGDIA mutation that causes SRNS. We demonstrated that ARHGDIA is in a complex with RHO GTPases and is prominently expressed in podocytes of rat glomeruli. ARHGDIA mutations (R120X and G173V) from individuals with SRNS abrogated interaction with RHO GTPases and increased active GTP-bound RAC1 and CDC42, but not RHOA, indicating that RAC1 and CDC42 are more relevant to the pathogenesis of this SRNS variant than RHOA. Moreover, the mutations enhanced migration of cultured human podocytes; however, enhanced migration was reversed by treatment with RAC1 inhibitors. The nephrotic phenotype was recapitulated in arhgdia-deficient zebrafish. RAC1 inhibitors were partially effective in ameliorating arhgdia-associated defects. These findings identify a single-gene cause of NS and reveal that RHO GTPase signaling is a pathogenic mediator of SRNS.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Case-Control Studies
  • Cell Movement
  • Cells, Cultured
  • Chromosome Mapping
  • Consanguinity
  • Gene Knockdown Techniques
  • Genetic Association Studies
  • Homozygote
  • Humans
  • Mutation, Missense*
  • Nephrotic Syndrome / enzymology
  • Nephrotic Syndrome / genetics*
  • Nephrotic Syndrome / pathology
  • Podocytes / metabolism
  • Podocytes / physiology
  • Protein Binding
  • Protein Interaction Mapping
  • Protein Transport
  • Sequence Analysis, DNA
  • Signal Transduction*
  • Zebrafish
  • cdc42 GTP-Binding Protein / metabolism
  • rac1 GTP-Binding Protein / metabolism
  • rho Guanine Nucleotide Dissociation Inhibitor alpha / genetics*
  • rho Guanine Nucleotide Dissociation Inhibitor alpha / metabolism
  • rhoA GTP-Binding Protein / metabolism*


  • ARHGDIA protein, human
  • RAC1 protein, human
  • rho Guanine Nucleotide Dissociation Inhibitor alpha
  • RHOA protein, human
  • cdc42 GTP-Binding Protein
  • rac1 GTP-Binding Protein
  • rhoA GTP-Binding Protein