Aberrant Golgi Trafficking and Glycosylation in VPS13B-Deficient Cells: Implications for Key Glycoprotein Dysfunction in Cohen Syndrome (the GlyCoS project)

Cohen syndrome is a rare genetic disorder that affects brain development, vision, muscle tone and immunity. It is caused by defects in a gene called VPS13B, which helps maintain the normal structure and function of the Golgi apparatus, a compartment inside the cell that processes and sorts many proteins. Previous studies indicate that in Cohen syndrome the Golgi apparatus becomes fragmented and functionally impaired, suggesting that protein glycosylation may also be altered. Indeed, glycan processing in the Golgi is essential for the correct folding, trafficking, and function of many proteins. In our patients, we found abnormal sugar patterns in serum proteins and in skin cells, even though standard laboratory tests used for classical glycosylation disorders were mostly normal. This suggests that Cohen syndrome may involve a more selective and previously unrecognized defect in protein glycosylation. The GlyCoS project will study how loss of VPS13B alters glycosylation and protein trafficking inside the cell. We will analyze cells from patients and laboratory cell models lacking VPS13B. Using advanced biochemical and imaging methods, we will test whether delayed protein-trafficking or aberrant routing leads to abnormal glycosylation of specific proteins, including LAMP-1 and alpha-dystroglycan. These cargos are informative because they may reveal how altered Golgi trafficking affects both general cargo processing and disease-relevant glycoprotein function in Cohen syndrome. This project is important because it may redefine Cohen syndrome as a Golgi-related trafficking disorder that drives selective glycosylation defects. Ultimately, these findings may facilitate the development of improved diagnostic tools, longitudinal biomarkers, and novel strategies to target underlying cellular defects.