Why this study matters

Cohen syndrome is a rare inherited condition caused by disease-causing variants in VPS13B. People with Cohen syndrome can experience developmental delay, small head size (microcephaly), characteristic facial features, low white blood cell counts, and progressive retinal degeneration that can affect vision over time. Although the genetic cause has been known for years, researchers are still working to understand how loss of VPS13B changes the behavior of cells—and how those cellular changes may contribute to disease.

A 2026 study in Cells offers a closer look at this question. The researchers created human cell lines lacking VPS13B and found coordinated problems involving cell growth, the Golgi apparatus, endoplasmic reticulum (ER), mitochondria, and cellular waste-processing pathways. Together, the findings suggest that VPS13B is important for maintaining the health and organization of several cellular systems at once.

Building a laboratory model of VPS13B deficiency

The team used CRISPR-Cas9 gene editing to remove exons 2 through 4 of VPS13B in Phoenix HEK293 cells, a human cell line commonly used in laboratory research. They generated five separate VPS13B knockout clones. Studying several independently created cell lines is important because it helps show that the observed effects are linked to VPS13B loss rather than to an unrelated change in a single clone.

This model does not reproduce every feature of Cohen syndrome, and these were not retinal cells or brain cells. However, it provided a controlled way to identify fundamental cellular consequences of VPS13B disruption.

VPS13B loss slowed cell growth

One of the clearest findings was that all VPS13B-deficient cell lines grew more slowly than control cells. The slowdown was linked to a longer G1 phase, the stage of the cell cycle during which cells prepare to copy their DNA and divide.

The researchers also found increased expression of CDKN1A, also known as p21. This gene encodes a protein that can slow cell-cycle progression, consistent with the observed G1 delay. While these results do not establish how altered cell-cycle timing contributes to Cohen syndrome in the body, they identify a reproducible cellular effect of VPS13B loss.

Multiple organelles showed signs of stress

Cells depend on specialized internal structures, called organelles, to make proteins, manage lipids, generate energy, and recycle damaged materials. In the VPS13B knockout cells, several of these systems appeared disrupted.

The Golgi apparatus—an organelle that modifies, sorts, and delivers proteins and lipids—was fragmented. Normally, VPS13B was found at the Golgi, but this localization was lost in mutant cells. This supports the idea that VPS13B has an important role in Golgi organization and trafficking.

The endoplasmic reticulum, or ER, also showed striking structural changes. Electron microscopy revealed widened ER compartments and unusually rigid-looking membranes. The ER is central to protein production and membrane lipid balance, so changes in its shape may signal difficulties in maintaining membrane health.

The study also identified signs of mitochondrial damage. Mitochondria provide much of the energy cells need, particularly in tissues with high energy demands. In addition, the researchers observed impaired autophagic maturation. Autophagy is the process by which cells package and break down damaged components; disrupted maturation may make it harder for cells to clear cellular material efficiently.

Fibrillary inclusions point to altered protein handling

A particularly notable observation was the presence of cytoplasmic fibrillary inclusion bodies in VPS13B-deficient cells. These structures were absent from control cells and were located close to the ER. Inclusion bodies can reflect changes in how cells manage proteins or other materials that are not being processed normally.

RNA sequencing added further evidence of cellular stress. Across four mutant clones, the researchers found 27 genes with consistently altered expression. These included reduced expression of genes related to transcriptional regulation, lipid metabolism, and neuronal signaling. Two stress-associated genes, CLU and CDKN1A, were increased.

Importantly, the findings did not support activation of the classical unfolded protein response, a well-known ER stress pathway. Instead, the authors propose that lipid bilayer stress and disrupted communication or trafficking between the ER and Golgi may be more relevant explanations for the changes they observed.

What could this mean for future treatments?

This work does not identify a treatment, but it helps define biological processes that future therapies may need to address. If VPS13B deficiency disrupts Golgi function, ER-Golgi trafficking, membrane lipid balance, autophagy, and cell-cycle control, researchers can begin testing whether these pathways are altered in more disease-relevant models, including retinal and neuronal cells.

The study also provides measurable features—such as Golgi fragmentation, ER changes, slower proliferation, and stress-gene activity—that could be used in future laboratory studies to evaluate potential interventions. Such cellular markers can help researchers determine whether a treatment candidate improves consequences of VPS13B loss.

Looking ahead

Cohen syndrome research is moving beyond identifying the responsible gene toward understanding the connected cellular effects of VPS13B deficiency. This study suggests that the condition may involve broad challenges in organelle homeostasis: the ability of cells to keep internal structures organized, functioning, and balanced.

The next important step will be to test these findings in cell types most relevant to Cohen syndrome, especially retinal and neural models. By connecting VPS13B loss to specific cellular pathways, studies like this one create a stronger foundation for future research aimed at protecting vision and improving outcomes for people living with Cohen syndrome.