Cohen syndrome is associated with major glycosylation defects

Cohen syndrome (CS) is a rare autosomal recessive disorder with multisytemic clinical features due to mutations in theVPS13Bgene, which has recently been describedencoding amandatorymembrane protein involved in Golgi integrity. As the Golgi complex is the place where glycosylation of newly synthesized proteins occurs, we hypothesized that VPS13B deficiency, responsible of Golgi apparatus disturbance, could lead to glycosylation defects and/or mysfunction of this organelle, and thus be a cause of the main clinical manifestations of CS. Theglycosylation status ofCSserumproteinsshowedaveryunusual pattern of glycosylation characterizedbya significant accumulationof agalactosylated fucosylated structures as well as asialylatedfucosylated structures demonstrating amajor defect of glycan maturation in CS. However, CS transferrin and a1-AT profiles, two liverderived proteins, were normal. We also showed that intercellular cell adhesion molecule 1 and LAMP-2, two highly glycosylated cellular proteins, presented an altered migration profile on SDS-PAGE in peripheral blood mononuclear cells from CS patients. RNA interference against VPS13B confirmed these glycosylation defects. Experiments with Brefeldin A demonstrated that intracellular retrograde cell trafficking was normal in CSfibroblasts. Furthermore, early endosomeswere almost absent in these cells and lysosomes were abnormally enlarged, suggesting a crucial role of VPS13B in endosomal-lysosomal trafficking. Our work provides evidence that CS is associated to a tissue-specific major defect of glycosylation and endosomal-lysosomal trafficking defect, suggesting that this could be a new key element to decipher the mechanisms of CS physiopathology.