Description:
Focal segmental glomerulosclerosis (FSGS) is a significant cause of human kidney disease. Mutations in the actin‐crosslinking protein alpha‐actinin‐4 (ACTN4) constitute a rare cause of glomerular podocyte damage and consequent FSGS. To this end, we report here a novel ACTN4 mutation that occurs at the tyrosine phosphorylation site, Y265H. This mutation was identified in a sporadic FSGS patient through exome sequencing and validated through Sanger sequencing. Using purified protein, we found that compared to WT ACTN4, Y265H ACTN4 mutant protein increased binding affinity to F‐actin. In immortalized human podocytes, transfection with mutant Y265H ACTN4 resulted in abnormal ACTN4 aggregation in the cytosol. These structural changes were associated with a two‐fold enhancement in traction forces that the podocytes exerted on their underlying substrate measured by traction force microscopy. Taken together, we demonstrate that a point mutation at an ACTN4 phosphorylation site can lead to aberrant biochemical and biophysical changes in the podocyte. Moreover, the Y265H mutation could be a novel ACTN4 mutation leading to FSGS in humans.