Cohen syndrome is associated with major glycosylation defects

ABSTRACT Cohen syndrome (CS) is a rare autosomal recessive disorder with multisytemic clinical features due to mutations in the VPS13B gene, which has recently been described encoding a mandatory membrane 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. The glycosylation status of CS serum proteins showed a very unusual pattern of glycosylation characterized by a significant accumulation of agalactosylated fucosylated structures as well as asialylated fucosylated structures demonstrating a major defect of glycan maturation in CS. However, CS transferrin and 1-AT profiles, two liver derived proteins, were normal. We also showed that ICAM-1 and LAMP-2, two highly glycosylated cellular proteins, presented an altered migration profile on SDS-polyacrylamide gels in peripheral blood mononuclear cells (PBMCs) from CS patients. RNA interference against