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Cohen syndrome is associated with major glycosylation defects.

Authors
  • Duplomb, Laurence
  • Duvet, Sandrine
  • Picot, Damien
  • Jego, Gaëtan
  • El Chehadeh-Djebbar, Salima
  • Marle, Nathalie
  • Gigot, Nadège
  • Aral, Bernard
  • Carmignac, Virginie
  • Thevenon, Julien
  • Lopez, Estelle
  • Rivière, Jean-Baptiste
  • Klein, André
  • Philippe, Christophe
  • Droin, Nathalie
  • Blair, Edward
  • Girodon, François
  • Donadieu, Jean
  • Bellanné-Chantelot, Christine
  • Delva, Laurent
  • And 5 more
Type
Published Article
Journal
Human Molecular Genetics
Publisher
Oxford University Press
Publication Date
May 01, 2014
Volume
23
Issue
9
Pages
2391–2399
Identifiers
DOI: 10.1093/hmg/ddt630
PMID: 24334764
Source
Medline
License
Unknown

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.

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