title: 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 α1-AT profiles, two liver-derived 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 CS fibroblasts. Furthermore, early endosomes were 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.
authors: Génétique et Anomalies du Développement, EA4271, Université de Bourgogne, Dijon, France.
authors: Laurence
authors: L
authors: Duplomb
authors: Sandrine
authors: S
authors: Duvet
authors: Damien
authors: D
authors: Picot
authors: Gaëtan
authors: G
authors: Jego
authors: Salima
authors: S
authors: El Chehadeh-Djebbar
authors: Nathalie
authors: N
authors: Marle
authors: Nadège
authors: N
authors: Gigot
authors: Bernard
authors: B
authors: Aral
authors: Virginie
authors: V
authors: Carmignac
authors: Julien
authors: J
authors: Thevenon
authors: Estelle
authors: E
authors: Lopez
authors: Jean-Baptiste
authors: JB
authors: Rivière
authors: André
authors: A
authors: Klein
authors: Christophe
authors: C
authors: Philippe
authors: Nathalie
authors: N
authors: Droin
authors: Edward
authors: E
authors: Blair
authors: François
authors: F
authors: Girodon
authors: Jean
authors: J
authors: Donadieu
authors: Christine
authors: C
authors: Bellanné-Chantelot
authors: Laurent
authors: L
authors: Delva
authors: Jean-Claude
authors: JC
authors: Michalski
authors: Eric
authors: E
authors: Solary
authors: Laurence
authors: L
authors: Faivre
authors: François
authors: F
authors: Foulquier
authors: Christel
authors: C
authors: Thauvin-Robinet
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002658:Developmental Disabilities / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D005347:Fibroblasts / Q000378:metabolism; D005385:Fingers / Q000002:abnormalities*; D006031:Glycosylation; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D008607:Intellectual Disability / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008831:Microcephaly / Q000378:metabolism*; D009123:Muscle Hypotonia / Q000378:metabolism*; D009216:Myopia / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*; D034622:RNA Interference; D012162:Retinal Degeneration; D014168:Transferrin / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D015815:Cell Adhesion Molecules; C065289:ICAM2 protein, human; D014168:Transferrin; C475722:VPS13B protein, human; D033921:Vesicular Transport Proteins; D018799:Intercellular Adhesion Molecule-1