FAT1 mutations cause a glomerulotubular nephropathy

Nat Commun. 2016 Feb 24:7:10822. doi: 10.1038/ncomms10822.


Steroid-resistant nephrotic syndrome (SRNS) causes 15% of chronic kidney disease (CKD). Here we show that recessive mutations in FAT1 cause a distinct renal disease entity in four families with a combination of SRNS, tubular ectasia, haematuria and facultative neurological involvement. Loss of FAT1 results in decreased cell adhesion and migration in fibroblasts and podocytes and the decreased migration is partially reversed by a RAC1/CDC42 activator. Podocyte-specific deletion of Fat1 in mice induces abnormal glomerular filtration barrier development, leading to podocyte foot process effacement. Knockdown of Fat1 in renal tubular cells reduces migration, decreases active RAC1 and CDC42, and induces defects in lumen formation. Knockdown of fat1 in zebrafish causes pronephric cysts, which is partially rescued by RAC1/CDC42 activators, confirming a role of the two small GTPases in the pathogenesis. These findings provide new insights into the pathogenesis of SRNS and tubulopathy, linking FAT1 and RAC1/CDC42 to podocyte and tubular cell function.

Publication types

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

MeSH terms

  • Animals
  • Cadherins / genetics*
  • Cell Adhesion / genetics*
  • Cell Movement / genetics*
  • Dilatation, Pathologic / genetics
  • Fibroblasts / metabolism*
  • Gene Knockdown Techniques
  • Hematuria / genetics
  • Humans
  • Kidney Tubules / cytology
  • Kidney Tubules / metabolism
  • Kidney Tubules / pathology
  • Lissencephaly / genetics
  • Mice
  • Mutation
  • Nephrotic Syndrome / congenital*
  • Nephrotic Syndrome / genetics
  • Podocytes / metabolism*
  • Syndrome
  • Zebrafish
  • Zebrafish Proteins / genetics*
  • cdc42 GTP-Binding Protein / metabolism
  • rac1 GTP-Binding Protein / metabolism


  • Cadherins
  • FAT1 protein, human
  • Zebrafish Proteins
  • fat1 protein, mouse
  • fat1a protein, zebrafish
  • cdc42 GTP-Binding Protein
  • rac1 GTP-Binding Protein

Supplementary concepts

  • Nephrotic syndrome, idiopathic, steroid-resistant