Loss of VPS13B protein in cells causes stress in cell compartments, slower cell division, and formation of fibrous clumps linked to Cohen Syndrome

VPS13B disruption in HEK293 cells led to a marked slowing of cell proliferation due to prolongation of the G1 phase.

• Cohen syndrome is linked to pathogenic variants in VPS13B, resulting in microcephaly, developmental delay, and progressive retinal degeneration.
• Five independent knockout clones demonstrated that VPS13B mutations caused fragmentation of the Golgi apparatus and loss of VPS13B localization to the Golgi.
• Cellular changes included ER lumen dilation, mitochondrial damage, impaired autophagic maturation, and the formation of cytoplasmic fibrillary inclusions.
• RNA sequencing revealed 27 differentially expressed genes in knockout clones, indicating downregulation of genes related to transcription, lipid metabolism, and neuronal signaling.
• Upregulation of stress-response genes CLU and CDKN1A (p21) was also observed, suggesting potential stress-related pathways involved in the disease.
• Findings indicate that VPS13B deficiency may lead to defects in organelle homeostasis, proteostasis, and cell-cycle progression.

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