Patients with ACTN4 mutations demonstrate distinctive features of glomerular injury.
Mutations in ACTN4, the gene encoding the actin-binding protein alpha-actinin-4, are a cause of familial FSGS. We examined kidney biopsies from patients with ACTN4 mutations to characterize systematically the histopathology of kidney damage in these patients and to determine whether distinctive morphologic changes are associated with mutations in this gene. The changes observed with light microscopy were typical of FSGS and were morphologically heterogeneous, similar to other inherited podocytopathies. The ultrastructural characteristics, however, were distinctive: Most notably, the presence of cytoplasmic electron-dense aggregates in podocytes. Indirect immunofluorescence using antibodies to a conserved domain of alpha-actinin-4 (present in both wild-type and mutant proteins) revealed a segmental and irregular granular staining pattern in the capillary walls of preserved glomeruli of ACTN4 mutants, whereas preserved glomeruli of patients with other podocyte diseases retained a global linear staining pattern for alpha-actinin-4. These characteristics resemble features observed in mouse models of this disease and may aid in the identification of patients and families who harbor ACTN4 mutations.
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Joel M
JM
Henderson
Mariam P
MP
Alexander
Martin R
MR
Pollak
D000185:Actinin / Q000032:analysis / Q000235:genetics*; D001706:Biopsy; D017124:Conserved Sequence; D019084:Fluorescent Antibody Technique, Indirect; D005799:Genes, Dominant; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007678:Kidney Glomerulus / Q000293:injuries* / Q000473:pathology* / Q000648:ultrastructure; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D009154:Mutation; D050199:Podocytes / Q000473:pathology / Q000502:physiology
C111453:ACTN4 protein, human; D000185:Actinin