What question did this study set out to answer?

Investigate the effects of a SAMD9L missense mutation on kidney disease and c-Myc activation in a mouse model.

March 28, 2026Kidney International Reports0 citationsOpen Access

WCN26-5934 A SAMD9L missense mutation drives autosomal dominant cystic kidney disease and c-Myc activation in mice

HHHomza HireedNorthwestern University DKDorian KaminskyYale University JWJoshua S. WaitzmanBeth Israel Deaconess Medical Center

Key Points

Investigate the effects of a SAMD9L missense mutation on kidney disease and c-Myc activation in a mouse model.
Utilized live imaging to assess lysosomal vesicle motility in cells with INF2 variants.
Conducted SEM analysis on INF2 variant cells to evaluate ER morphology and cytoskeletal organization.
Analyzed mitochondrial fragmentation and actin-microtubule network disruptions in various disease variants.
The INF2 variant cells exhibited marked changes in ER morphology, including a sheet-like appearance.
Lysosomal vesicle motility was significantly reduced in INF2 variant expressing cells (p<0.0001).
Cytoskeletal disruptions were evident in INF2 variants, with severe implications for organelle interactions.

Abstract

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.

问 AI

Bookmark

View Full Paper