Missense Mutant Gain-of-Function Causes Inverted Formin 2 (INF2)-Related Focal Segmental Glomerulosclerosis (FSGS).

Area of Science:

• Nephrology
• Genetics
• Cell Biology

Background:

• Inverted formin-2 (INF2) mutations are a common cause of genetic focal segmental glomerulosclerosis (FSGS), often with Charcot-Marie-Tooth (CMT) disease.
• INF2 regulates actin and microtubules, impacting cell adhesion, mitochondrial function, and vesicle trafficking.
• The exact mechanism linking INF2 mutations to FSGS pathogenesis and inheritance patterns remains unclear.

Purpose of the Study:

• To investigate the pathogenic mechanism of INF2 mutations in FSGS.
• To compare the kidney phenotypes of INF2 point mutant knock-in and knock-out mouse models.
• To elucidate the role of INF2 gain-of-function in FSGS development and inheritance.

Main Methods:

• Generated and analyzed R218Q INF2 point mutant knock-in and INF2 knock-out mouse models.
• Induced kidney injury using puromycin aminonucleoside (PAN).
• Performed co-localization, co-immunoprecipitation, actin content analysis, and RNA expression profiling. Studied patient-derived podocytes.

Main Results:

• R218Q INF2 mice developed proteinuria and FSGS, unlike INF2 knock-out mice with minimal kidney phenotype.
• The R218Q INF2 mutation confers a gain-of-function, altering the actin cytoskeleton and INF2 localization.
• Adhesion and mitochondria pathways were enriched in diseased glomeruli, and mutant podocytes showed defective adhesion and mitochondrial function.

Conclusions:

• Gain-of-function mechanisms of INF2 drive FSGS pathogenesis.
• Altered actin cytoskeleton and cellular processes contribute to glomerular disease.
• This study explains the autosomal dominant inheritance pattern observed in INF2-related FSGS.