Variable renal phenotype in a family with an INF2 mutation

Area of Science:

• Nephrology
• Genetics
• Molecular Biology

Background:

• Glomerular diseases, including nephrotic syndrome and proteinuria, are increasingly linked to specific gene mutations.
• The INF2 gene, encoding an actin-regulating protein, was identified in 2010 as a cause of autosomal dominant focal segmental glomerulosclerosis (FSGS).

Observation:

• This report details a family with three members (two siblings and their father) carrying a heterozygous p.E220K mutation in the INF2 gene.
• The mutation presented with proteinuria at different ages (7, 9, and 30 years) and varied in severity, with siblings experiencing nephrotic range proteinuria and one progressing to end-stage renal disease.
• The father exhibited only mild proteinuria and maintained normal renal function into adulthood.

Findings:

• Renal biopsy in one sibling confirmed FSGS, characterized by irregular podocyte foot process morphology and focal glomerular basement membrane abnormalities.
• This case represents the second documented familial FSGS linked to INF2 mutations.
• Significant intrafamilial phenotypic variability was observed, despite the shared INF2 mutation.

Implications:

• The findings reinforce the role of INF2 mutations in the pathogenesis of familial FSGS.
• Understanding the genetic basis and variable expressivity of INF2-associated FSGS is crucial for diagnosis and management.
• Further research into the mechanisms underlying intrafamilial variability may reveal novel therapeutic targets for glomerular diseases.