leaving some sheet-like appearance in perinuclear regions.FSGS-single disease variants retained the ER pattern but displayed more sheet-like appearance.In contrast, FSGS/CMT variant cells had a marked tubuleto-sheet transition in the peripheral ER, as well as retraction form cell edges with deposition of INF2 aggregates, resulting from disarranged actin and microtubule networks.Mitochondrial fragmentation and peripheral mis-distribution were more severe in FSGS/CMT variants than in FSGS variants.Live imaging revealed a reduced lysosomal vesicle motility in INF2 variant expressing cells (n=100, p<0.0001) and increased the ER-mitochondria contact sites.SEM analysis with sections of INF2 variant cells revealed a prevalent sheet-like ER pattern with and disrupted actin-microtubule network, indicating impaired ER interfaces with other organelles.Conclusion: Pathogenic INF2 variants impair cytoskeletal architecture and ER-organelle contact sites, generating a spectrum of pathogenic effect from FSGS (mild) to FSGS/CMT variants (severe).High resolution, live-cell imaging revealed previously unrecognize alterations, including shortened actin bundles, elongated filopodia, and dysmorphic mitochondria.These findings support a shared mechanism involving cytoskeletal collapse and organelle dysfunction among INF2disorders.Further study is needed to define the tissue-specific, cofactors that modulate deleterious effects of variants in podocyte or neuron.I have no potential conflict of interest to disclose.I did not use generative AI and AI-assisted technologies in the writing process.
Hireed et al. (Wed,) studied this question.