Open AccessMutations in INF2 Are a Major Cause of Autosomal Dominant Focal Segmental Glomerulosclerosis
Author(s) -
Olivia Boyer,
Geneviève Benoît,
Olivier Gribouval,
Fabien Névo,
Marie-Josèphe Tête,
Jacques Dantal,
Brigitte GilbertDussardier,
Guy Touchard,
Alexandre Karras,
Claire Presne,
JeanPierre Grünfeld,
Christophe Legendre,
Dominique Joly,
Philippe Rieu,
Nabil Mohsin,
Thierry Hannedouche,
Valérie Moal,
Marie–Claire Gubler,
Isabelle Broutin,
Géraldine Mollet,
Corinne Antignac
Publication year - 2011
Publication title -
journal of the american society of nephrology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.451
H-Index - 279
eISSN - 1533-3450
pISSN - 1046-6673
DOI - 10.1681/asn.2010050518
Subject(s) - formins , podocyte , focal segmental glomerulosclerosis , nephrin , biology , actin , slit diaphragm , actin cytoskeleton , mutation , genetics , semaphorin , missense mutation , haploinsufficiency , microbiology and biotechnology , gene , cytoskeleton , receptor , glomerulonephritis , phenotype , kidney , proteinuria , cell
The recent identification of mutations in the INF2 gene, which encodes a member of the formin family of actin-regulating proteins, in cases of familial FSGS supports the importance of an intact actin cytoskeleton in podocyte function. To determine better the prevalence of INF2 mutations in autosomal dominant FSGS, we screened 54 families (78 patients) and detected mutations in 17% of them. All mutations were missense variants localized to the N-terminal diaphanous inhibitory domain of the protein, a region that interacts with the C-terminal diaphanous autoregulatory domain, thereby competing for actin monomer binding and inhibiting depolymerization. Six of the seven distinct altered residues localized to an INF2 region that corresponded to a subdomain of the mDia1 diaphanous inhibitory domain reported to co-immunoprecipitate with IQ motif-containing GTPase-activating protein 1 (IQGAP1). In addition, we evaluated 84 sporadic cases but detected a mutation in only one patient. In conclusion, mutations in INF2 are a major cause of autosomal dominant FSGS. Because IQGAP1 interacts with crucial podocyte proteins such as nephrin and PLCε1, the identification of mutations that may alter the putative INF2-IQGAP1 interaction provides additional insight into the pathophysiologic mechanisms linking formin proteins to podocyte dysfunction and FSGS.