Thus, this novel mutation in INF2 linked to nonsyndromic FSGS indicates the necessity for full gene sequencing if no mutation is found in the current rapid-screen region of the gene.
Mutations in inverted formin 2 (INF2), a member of the formin family of actin-regulating proteins, have recently been associated with a familial cause of nephrotic syndrome characterized by FSGS.
Recently, mutations in the INF2 gene, which encodes inverted formin-2, were identified in patients with focal segmental glomerulosclerosis and a dominant intermediate form of CMT (CMTDIE, OMIM #614455).
Physiologically, INF2 acts in the secretory pathway and is mutated in two human diseases, focal and segmental glomerulosclerosis and Charcot-Marie-Tooth disease.
We performed direct genotyping of INF2 in 16 index patients with Charcot-Marie-Tooth neuropathy and FSGS who did not have a mutation in PMP22 or MPZ, encoding peripheral myelin protein 22 and myelin protein zero, respectively.
Dominant missense mutations in INF2 are linked to two diseases: focal segmental glomerulosclerosis, a kidney disease, and Charcot-Marie-Tooth disease, a neuropathy.
INF2 mutations associated with dominant inherited intermediate Charcot-Marie-Tooth neuropathy with focal segmental glomerulosclerosis in two Chinese patients.
Heterozygous mutations in the inverted formin-2 (INF2) gene provoke focal segmental glomerulosclerosis (FSGS) and intermediate Charcot-Marie-Tooth (CMT) disease with FSGS.
Recent advances show that human focal segmental glomerulosclerosis (FSGS) is a primary podocytopathy caused by podocyte-specific gene mutations including NPHS1, NPHS2, WT-1, LAMB2, CD2AP, TRPC6, ACTN4 and INF2.
These mutations, all within the diaphanous inhibitory domain of INF2, segregate with FSGS in 11 unrelated families and alter highly conserved amino acid residues.
Mutational analysis of INF2 was performed on 109 patients (mean age at onset 41.44 ± 18.91 years) with FSGS or minimal change disease (MCD); and also in 6 patients without renal biopsy who had already developed chronic kidney disease (CKD)/ESRD at the time of diagnosis.
In this case series, we present 3 adult patients who presented with advanced renal disease with the histological picture of FSGS and proved to have a genetic cause of the disease, namely, variants in INF2, COL4A4 and HNF1B, respectively.
INF2 mutations in patients with isolated FSGS are clustered in exons 2 to 4, encoding the diaphanous inhibitory domain, involved in the regulation of the podocyte actin cytoskeleton.
These mutations, all within the diaphanous inhibitory domain of INF2, segregate with FSGS in 11 unrelated families and alter highly conserved amino acid residues.
In three distinct models of FSGS (5/6-nephrectomy + DOCA-salt; the murine transgenic chronic Thy1.1 model; or the MWF rat) and in human biopsies, the primary injury to induce FSGS associated with focal activation of PECs and the formation of cellular adhesions to the capillary tuft.