Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis

Focal and segmental glomerulosclerosis(1) (FSGS) is a common, non-specific renal lesion. Although it is often secondary to other disorders, including HIV infection, obesity, hypertension and diabetes, FSGS also appears as an isolated, idiopathic condition. FSGS is characterized by increased urinary protein excretion and decreasing kidney function. Often, renal insufficienc y in affected patients progresses to end-stage renal failure, a highly morb id state requiring either dialysis therapy or kidney transplantation. Here we present evidence implicating mutations in the gene encoding alpha-actini n-4 (ACTN4; ref. 2), an actin-filament crosslinking protein, as the cause o f disease in three families with an autosomal dominant form of FSCS. In vit ro, mutant alpha-actinin-4 binds filamentous actin (F-actin) more strongly than does wild-type alpha-actinin-4. Regulation of the actin cytoskeleton o f glomerular podocytes may be altered in this group of patients. Our result s have implications for understanding the role of the cytoskeleton in the p athophysiology of kidney disease and may lead to a better understanding of the genetic basis of susceptibility to kidney damage.