Mutations in the INF2 gene account for a significant proportion of familial but not sporadic focal and segmental glomerulosclerosis

Abstract

Mutations in the inverted formin 2 gene (INF2) have recently been identified as the most common cause of autosomal dominant focal and segmental glomerulosclerosis (FSGS). To quantify the contribution of various genes contributing to FSGS, we sequenced INF2 where all mutations have previously been described (exons 2 to 5) in a total of 215 probands and 281 sporadic individuals with FSGS, along with other known genes accounting for autosomal dominant FSGS (ACTN4, TRPC6, and CD2AP) in 213 probands. Variants were classified as disease-causing if they altered the amino acid sequence and if they were not found in control samples and in families segregated with disease. Mutations in INF2 were found in a total of 20 of the 215 families (including those previously reported) in our cohort of autosomal dominant familial nephrotic syndrome or FSGS, thereby explaining disease in 9%. INF2 mutations were found in 2 of 281 individuals with sporadic FSGS. In contrast, ACTN4- and TRPC6-related diseases accounted for 3 and 2% of our familial cohort, respectively. INF2-related disease showed variable penetrance, with onset of disease ranging widely from childhood to adulthood, and commonly leading to end-stage renal disease in the third and fourth decade of life. Thus, mutations in INF2 are a more common, although still a minor, monogenic cause of familial FSGS when compared with other known autosomal dominant genes associated with FSGS.

Figure 1

Summary of INF2 substitutions, with red representing affected residues reported in families with FSGS and green representing residues reported to be altered in individuals with CMT disease. Disease-segregating alterations shown aligned with wild-type INF2 protein sequence from humans, gorilla, bovine, horse, mouse and chicken. All of the disease alterations occur in evolutionarily conserved residues.

Figure 2

(a) Schematic showing INF2 protein domain structure. All INF2 mutations identified thus far occur in exons 2 to 4, which localizes to the diaphanous inhibitory domain (DID) of the protein, albeit only exons 2 to 5 were sequenced in the majority of individuals in our cohort. FH1/2 = formin homology domains 1 and 2, DAD = diaphanous activating domain (b) Three dimensional model of the first 234 amino acids of INF2 as modeled in Phyre^2. Affected residues identified in families with FSGS are indicated in red. All known pathogenic mutations cluster in the DID, represented by grey ribbons. Green represents residues mutated in individuals with CMT disease. Figure was generated using PyMOL (DeLano, W.L. The PyMOL molecular graphics system 2002).