Alpha-actinin-4-mediated FSGS: an inherited kidney disease caused by an aggregated and rapidly degraded cytoskeletal protein

PLoS Biol. 2004 Jun;2(6):e167. doi: 10.1371/journal.pbio.0020167. Epub 2004 Jun 15.


Focal segmental glomerulosclerosis (FSGS) is a common pattern of renal injury, seen as both a primary disorder and as a consequence of underlying insults such as diabetes, HIV infection, and hypertension. Point mutations in the alpha-actinin-4 gene ACTN4 cause an autosomal dominant form of human FSGS. We characterized the biological effect of these mutations by biochemical assays, cell-based studies, and the development of a new mouse model. We found that a fraction of the mutant protein forms large aggregates with a high sedimentation coefficient. Localization of mutant alpha-actinin-4 in transfected and injected cells, as well as in situ glomeruli, showed aggregates of the mutant protein. Video microscopy showed the mutant alpha-actinin-4 to be markedly less dynamic than the wild-type protein. We developed a "knockin" mouse model by replacing Actn4 with a copy of the gene bearing an FSGS-associated point mutation. We used cells from these mice to show increased degradation of mutant alpha-actinin-4, mediated, at least in part, by the ubiquitin-proteasome pathway. We correlate these findings with studies of alpha-actinin-4 expression in human samples. "Knockin" mice with a disease-associated Actn4 mutation develop a phenotype similar to that observed in humans. Comparison of the phenotype in wild-type, heterozygous, and homozygous Actn4 "knockin" and "knockout" mice, together with our in vitro data, suggests that the phenotypes in mice and humans involve both gain-of-function and loss-of-function mechanisms.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Actinin / genetics*
  • Actinin / metabolism*
  • Animals
  • Base Sequence
  • Disease Models, Animal
  • Gene Components
  • Gene Expression Regulation / genetics*
  • Glomerulosclerosis, Focal Segmental / genetics*
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization
  • Kidney Glomerulus / ultrastructure
  • Mice
  • Mice, Mutant Strains
  • Microfilament Proteins / genetics*
  • Microscopy, Electron
  • Microscopy, Video
  • Mutation / genetics
  • Phenotype*
  • Transfection


  • ACTN4 protein, human
  • Microfilament Proteins
  • Actinin