INF2 – Autosomal Dominant Focal Segmental Glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) is a histopathologic pattern of podocyte injury leading to proteinuria and progressive renal failure. In 2010, linkage analysis pinpointed a susceptibility locus on chromosome 14q in families with autosomal dominant FSGS, and sequencing revealed nine independent nonconservative missense mutations in the diaphanous inhibitory domain of INF2 that segregate with disease in 11 unrelated families (PMID:20023659). Subsequent familial reports, including a three-member pedigree with a heterozygous c.658G>A (p.Glu220Lys) variant, demonstrated variable age of onset from childhood to adulthood and intrafamilial phenotypic variability in proteinuria and renal survival (PMID:20803156).

The spectrum of INF2 variants includes key diaphanous inhibitory domain missense changes, notably c.640C>T (p.Arg214Cys), as well as c.395T>C (p.Leu132Pro) and c.658G>A (p.Glu220Lys), all demonstrating autosomal dominant inheritance with full segregation and absence in population controls. A representative variant, c.640C>T (p.Arg214Cys), has been recurrently observed in multiple kindreds, supporting a mutational hotspot in exon 4 of INF2.

Functional studies have elucidated the pathogenic mechanism: INF2 localizes to the endoplasmic reticulum and modulates actin filament dynamics via its WH2/DAD motif (PMID:19366733). Disease-associated INF2 mutants perturb the INF2–mDia–RhoA axis, leading to disrupted actin polymerization, aberrant depolymerization, and mislocalization of cytoskeletal and slit-diaphragm proteins in podocytes (PMID:22187985; PMID:21278336). In vivo models confirm that INF2 mutations impair podocyte foot process recovery following injury and accelerate glomerular sclerosis.

No significant conflicting evidence has emerged, and multiple large cohorts and functional assays over more than a decade solidify INF2 as a definitive monogenic cause of FSGS. The integration of genetic and functional data underlines haploinsufficient and gain-of-function effects on actin regulation as central to disease pathogenesis.

Key Take-home: Autosomal dominant INF2 mutations causing dysregulated actin dynamics are a definitive cause of familial FSGS and warrant targeted genetic testing for accurate diagnosis, prognostication, and familial counseling.

References

• Nature genetics • 2010 • Mutations in the formin gene INF2 cause focal segmental glomerulosclerosis PMID:20023659
• Pediatric nephrology • 2011 • Variable renal phenotype in a family with an INF2 mutation. PMID:20803156
• The New England journal of medicine • 2011 • INF2 mutations in Charcot-Marie-Tooth disease with glomerulopathy. PMID:22187985
• Proceedings of the National Academy of Sciences of the United States of America • 2011 • Rho activation of mDia formins is modulated by an interaction with inverted formin 2 (INF2). PMID:21278336
• Journal of cell science • 2009 • INF2 is an endoplasmic reticulum-associated formin protein. PMID:19366733

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