alpha-actinin-4 is a member of the actinin protein family comprised of an actin-binding domain in the N-terminus, 4 spectrin-like repeats in the central region, and 2 EF-hand motifs in the C-terminus (Honda et al, 1998). alpha-actinin-4 and CLP36 form a complex in normal kidney podocytes.CLP36 is dependent on alpha-actinin-4 for maintenance of its level in podocytes, whereas alpha-actinin-4 is independent of CLP36. alpha-actinin-4 is widely expressed in mammalian tissues and organs, while having a high occurrence of genetic mutations in kidney podocytes (Kos et al, 2003). FSGS, focal segmental glomerulosclerosis, is a rare genetic disease that attacks the kidneys filtering units (glomeruli) causing serious scarring which leads to permanent kidney damage and even failure. Three key mutations have been found in alpha-actinin-4 in people diagnosed with FSGS. R310Q and Q348R, located in the spectrin-like repeats region, and K255E located in the actin-binding region. The R310Q and Q348R mutation significantly inhibits the ability of alpha-actinin-4 to form the complex with CLP36. The K255E mutation was reversed where it increased the ability to bind CLP36 in the actin-binding region (Liu et al, 2011).
