Mutations in the formin protein INF2 cause focal segmental glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) is a pattern of kidney injury observed either as an idiopathic finding or as a consequence of underlying systemic conditions. Several genes have been identified which, when mutated, lead to inherited FSGS and/or the nephrotic syndrome. These findings have accelerated the understanding of glomerular podocyte function and disease, motivating our search for additional FSGS genes. Using linkage analysis, we identified a locus for autosomal dominant FSGS on a region of chromosome 14q. By sequencing multiple genes in this region, we detected nine independent non-conservative missense mutations in INF2, which encodes a member of the formin family of actin regulating proteins. These mutations, all within the diaphanous inhibitory domain, segregate with disease in 11 unrelated families and alter highly conserved amino acid residues. The observation that mutations in this podocyte-expressed formin cause FSGS highlights the importance of fine regulation of actin polymerization in podocyte function.