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Abstract: SA-PO741

Disease-Associated Mutant Gain-of-Function Causes INF2-Related Focal Segmental Glomerulosclerosis

Session Information

Category: Glomerular Diseases

  • 1304 Glomerular Diseases: Podocyte Biology

Authors

  • Subramanian, Balaji karthick, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
  • Pollak, Martin, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States

Group or Team Name

  • BIDMC-Nephrology
Background

Highly penetrant Mendelian forms of Focal Segmental Glomerulosclerosis (FSGS) are rare examples where we can unequivocally say we know the cause of the disease. Inverted Formin 2 (INF2) is one of the 15 members of the formin family of proteins, which share a formin homology domain (FH2) involved in the control of actin polymerization. Missense mutations in INF2 lead to kidney disease characterized by proteinuria, progressive kidney dysfunction, and FSGS with or without Charcot–Marie–Tooth disease (CMT). Prior studies have suggested that INF2 promotes actin polymerization and modulates various cell processes such as mitochondria fission and Rho/mDIA signaling. However, the mechanisms underlying kidney disease development remain unclear.

Methods

INF2 knock-out and INF2 R218Q knock-in mouse models were compared for their disease phenotype development. Puromycin aminonucleoside (PAN) injury was used as a stress model to compare the disease development between INF2 knock-out and knock-in mice models. Glomerular RNA sequencing analyses were performed to identify the pathways associated with the disease development. Micropatterned podocytes were used to validate the pathways driving the disease development.

Results

Neither the INF2 R218Q knock-in mutation nor INF2 knock-out condition impact glomerular development. However, the disease phenotype was higher with PAN injury in heterozygous and homozygous R218Q INF2 knock-in mice. In contrast, heterozygous or homozygous knock-out mice do not develop any significant kidney disease phenotype. RNA sequencing analysis showed changes in the expression of genes that regulate cell adhesion, mitochondria, and trafficking to associate with the disease phenotype. These changes were replicated in micropatterned podocytes, in which heterozygous and homozygous knock-in mice-derived podocytes exhibited disease-associated cell-adhesion (cortactin distribution) and mitochondria (fission/fusion balance) and trafficking (lipid raft recycling) defects.

Conclusion

INF2 mutation confers susceptibility to glomerular injury in the mouse, indicating the gain-of-function nature of INF2 mutants and presenting an important model to target for therapeutics development. Processes associated with cell adhesion, trafficking, and mitochondria may be involved in the disease.

Funding

  • NIDDK Support