title: 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.
authors.affiliation: Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
authors.forename: Moumita
authors.initials: M
authors.lastname: Barua
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Brown
authors.forename: Victoria T
authors.initials: VT
authors.lastname: Charoonratana
authors.forename: Giulio
authors.initials: G
authors.lastname: Genovese
authors.forename: Hua
authors.initials: H
authors.lastname: Sun
authors.forename: Martin R
authors.initials: MR
authors.lastname: Pollak
mesh_terms: D000185:Actinin / Q000235:genetics; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D002648:Child; D003598:Cytoskeletal Proteins / Q000235:genetics; D000080865:Formins; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics*; D006801:Humans; D008840:Microfilament Proteins / Q000737:chemistry / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D050052:TRPC Cation Channels / Q000235:genetics; D000074287:TRPC6 Cation Channel
chemical_list: C111453:ACTN4 protein, human; D048868:Adaptor Proteins, Signal Transducing; C114545:CD2-associated protein; D003598:Cytoskeletal Proteins; D000080865:Formins; C546959:INF2 protein, human; D008840:Microfilament Proteins; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C117032:TRPC6 protein, human; D000185:Actinin