Cohen syndrome is associated with major glycosylation defects
Laurence Duplomb
(1, 2)
,
Sandrine Duvet
(3)
,
Damien Picot
(1)
,
Gaetan Jego
(4)
,
Salima El Chehadeh-Djebbar
(1, 2)
,
Nathalie Marle
(1, 2)
,
Nadège Gigot
(2, 1)
,
Bernard Aral
(1, 2)
,
Virginie Carmignac
(1)
,
Julien Thevenon
(1, 2)
,
Estelle Lopez
(1)
,
Jean Rivière
(1, 2)
,
André Klein
(5)
,
Christophe Philippe
(6, 7)
,
Nathalie Droin
(8)
,
Edward Blair
(9)
,
François Girodon
(10)
,
Jean Donadieu
(11)
,
Christine Bellanné-Chantelot
(12)
,
Laurent Delva
(4)
,
Jean-Claude Michalski
(3)
,
Eric Solary
(8, 13)
,
Laurence Faivre
(2, 1)
,
François Foulquier
(3)
,
Christel Thauvin-Robinet
(1, 2)
1
GAD -
Génétique des Anomalies du Développement
2 FHU TRANSLAD, Département de Génétique
3 UGSF - Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576
4 LNC - Lipides - Nutrition - Cancer (U866)
5 Laboratoire de Biochimie et de Biologie Moléculaire, UAM de glycopathologies
6 Service de Génétique [CHRU Nancy]
7 NGERE - Nutrition-Génétique et Exposition aux Risques Environnementaux
8 IGR - Institut Gustave Roussy
9 Department of Clinical Genetics, Oxford Regional Genetics Service
10 Service d'hématologie biologique [CHU de Dijon]
11 CHU Trousseau [APHP]
12 CHU Pitié-Salpêtrière [AP-HP]
13 Hématopoïèse normale et pathologique
2 FHU TRANSLAD, Département de Génétique
3 UGSF - Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576
4 LNC - Lipides - Nutrition - Cancer (U866)
5 Laboratoire de Biochimie et de Biologie Moléculaire, UAM de glycopathologies
6 Service de Génétique [CHRU Nancy]
7 NGERE - Nutrition-Génétique et Exposition aux Risques Environnementaux
8 IGR - Institut Gustave Roussy
9 Department of Clinical Genetics, Oxford Regional Genetics Service
10 Service d'hématologie biologique [CHU de Dijon]
11 CHU Trousseau [APHP]
12 CHU Pitié-Salpêtrière [AP-HP]
13 Hématopoïèse normale et pathologique
Estelle Lopez
- Fonction : Auteur
- PersonId : 183438
- IdHAL : taulan-magali
- ORCID : 0000-0003-0059-9394
- IdRef : 080164501
Jean Rivière
- Fonction : Auteur
- PersonId : 12380
- IdHAL : jean-riviere
- ORCID : 0000-0001-5004-2290
- IdRef : 103777474
André Klein
- Fonction : Auteur
- PersonId : 834480
Christophe Philippe
- Fonction : Auteur
- PersonId : 761163
- IdRef : 083945237
Nathalie Droin
- Fonction : Auteur
- PersonId : 770388
- IdHAL : nathalie-droin-44106
- ORCID : 0000-0002-6099-5324
- IdRef : 176330593
François Girodon
- Fonction : Auteur
- PersonId : 860217
Christine Bellanné-Chantelot
- Fonction : Auteur
- PersonId : 757816
- ORCID : 0000-0001-8415-6771
- IdRef : 18315438X
Eric Solary
- Fonction : Auteur
- PersonId : 757151
- IdHAL : eric-solary
- ORCID : 0000-0002-8629-1341
- IdRef : 050500031
Laurence Faivre
- Fonction : Auteur
- PersonId : 856301
François Foulquier
- Fonction : Auteur
- PersonId : 748197
- IdHAL : francois-foulquier
Christel Thauvin-Robinet
- Fonction : Auteur
- PersonId : 994672
Résumé
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.