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Characterization of cytoskeletal and structural effects of INF2 variants causing glomerulopathy and neuropathy

Hiroko Ueda1, Quynh Thuy Huong Tran1, Linh Nguyen Truc Tran1

  • 1Division of Nephrology, Second Department of Internal Medicine, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1191, Japan.

Scientific Reports
|July 25, 2023
PubMed

Insights

INF2 gene variants cause kidney disease (FSGS) and nerve disorders (CMT/FSGS). CMT/FSGS variants disrupt cell structures more severely than FSGS variants, impacting mitochondria and cellular integrity.

Area of Science:

  • Nephrology
  • Genetics
  • Cell Biology

Background:

  • Focal segmental glomerulosclerosis (FSGS) is a major cause of end-stage renal disease, often linked to podocyte dysfunction.
  • Monogenic FSGS arises from genetic defects, particularly in the INF2 gene, which affects actin dynamics.
  • INF2 variants can lead to isolated FSGS or a combined Charcot-Marie-Tooth disease and FSGS (CMT/FSGS) phenotype.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying INF2-related disorders by comparing FSGS and CMT/FSGS variants.
  • To investigate the structural and cytoskeletal consequences of specific INF2 variants.

Main Methods:

  • Molecular dynamics simulations were used to analyze the flexibility and stability of wild-type and variant INF2 proteins.
  • Immunocytochemistry was employed to assess cytoskeletal organization (actin stress fibers, microtubules) and mitochondrial morphology in cells expressing INF2 variants.

Main Results:

  • All analyzed INF2 variants exhibited altered flexibility compared to wild-type, potentially affecting intramolecular interactions.
  • INF2 variants led to reduced actin stress fibers and disorganized microtubule arrays.
  • CMT/FSGS variants induced more significant mitochondrial fragmentation and altered distribution than FSGS variants, correlating with cytoskeletal disruption severity.

Conclusions:

  • INF2 variants associated with CMT/FSGS cause more profound cellular defects, including disrupted cytoskeleton-organelle interactions, compared to FSGS-only variants.
  • The findings highlight distinct cellular impacts of INF2 variants, suggesting different pathogenic pathways for FSGS and CMT/FSGS.
  • Further research is required to understand tissue-specific mechanisms and cellular functions involved in these complex disorders.

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