INF2 mutations cause kidney disease through a gain-of-function mechanism

Area of Science:

• Nephrology
• Genetics
• Cell Biology

Background:

• Mutations in inverted formin-2 (INF2) are linked to focal segmental glomerulosclerosis (FSGS), a kidney disorder.
• The precise mechanism, gain-of-function or loss-of-function, underlying INF2-related FSGS remains unclear.
• INF2 knockout mice and mice with a disease-associated mutation lack overt kidney or neurological phenotypes.

Purpose of the Study:

• To investigate the pathogenic mechanism of INF2 mutations in FSGS.
• To determine whether INF2 mutations cause disease through gain-of-function or loss-of-function effects.
• To elucidate the role of INF2 in kidney injury and disease development.

Main Methods:

• Comparison of puromycin aminonucleoside (PAN)-induced kidney injury in INF2 R218Q mutant mice and INF2 knockout mice.
• Assessment of INF2's effect on the actin cytoskeleton using colocalization, coimmunoprecipitation, and actin measurements.
• Analysis of RNA expression in PAN-treated R218Q mice to identify enriched pathways.
• Phenotypic analysis of podocytes from R218Q mice and human kidney organoids with INF2 mutations.

Main Results:

• INF2 R218Q mutant mice, unlike INF2 knockout mice, exhibited susceptibility to glomerular disease after PAN treatment.
• The INF2 R218Q mutation demonstrated a gain-of-function effect on the actin cytoskeleton.
• PAN-treated R218Q mice showed enrichment in adhesion and mitochondria-related pathways.
• Podocytes from R218Q mice and human kidney organoids with INF2 mutations recapitulated adhesion and mitochondrial defects.

Conclusions:

• Gain-of-function mechanisms involving the actin cytoskeleton are the primary drivers of INF2-related FSGS.
• These findings explain the autosomal dominant inheritance pattern observed in INF2-related FSGS.
• INF2's role in actin dynamics is critical for maintaining podocyte integrity and kidney function.