A homozygous missense mutation in the ciliary gene TTC21B causes familial FSGS

J Am Soc Nephrol. 2014 Nov;25(11):2435-43. doi: 10.1681/ASN.2013101126. Epub 2014 May 29.


Several genes, mainly involved in podocyte cytoskeleton regulation, have been implicated in familial forms of primary FSGS. We identified a homozygous missense mutation (p.P209L) in the TTC21B gene in seven families with FSGS. Mutations in this ciliary gene were previously reported to cause nephronophthisis, a chronic tubulointerstitial nephropathy. Notably, tubular basement membrane thickening reminiscent of that observed in nephronophthisis was present in patients with FSGS and the p.P209L mutation. We demonstrated that the TTC21B gene product IFT139, an intraflagellar transport-A component, mainly localizes at the base of the primary cilium in developing podocytes from human fetal tissue and in undifferentiated cultured podocytes. In contrast, in nonciliated adult podocytes and differentiated cultured cells, IFT139 relocalized along the extended microtubule network. We further showed that knockdown of IFT139 in podocytes leads to primary cilia defects, abnormal cell migration, and cytoskeleton alterations, which can be partially rescued by p.P209L overexpression, indicating its hypomorphic effect. Our results demonstrate the involvement of a ciliary gene in a glomerular disorder and point to a critical function of IFT139 in podocytes. Altogether, these data suggest that this homozygous TTC21B p.P209L mutation leads to a novel hereditary kidney disorder with both glomerular and tubulointerstitial damages.

Keywords: focal segmental glomerulosclerosis; genetic renal disease; nephronophthisis; podocyte.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adolescent
  • Adult
  • Animals
  • Cell Line, Transformed
  • Child
  • Cilia / pathology
  • Cilia / physiology*
  • Family Health
  • Female
  • Glomerulosclerosis, Focal Segmental / genetics*
  • Glomerulosclerosis, Focal Segmental / pathology
  • Haplotypes
  • Homozygote
  • Humans
  • Male
  • Mice
  • Microtubule-Associated Proteins / genetics*
  • Mutation, Missense
  • Pedigree
  • Phenotype
  • Podocytes / pathology
  • Podocytes / physiology*
  • Stress Fibers / pathology
  • Stress Fibers / physiology
  • Young Adult


  • Adaptor Proteins, Signal Transducing
  • Microtubule-Associated Proteins
  • TTC21B protein, human