title: Golgi GDP-fucose transporter-deficient mice mimic congenital disorder of glycosylation IIc/leukocyte adhesion deficiency II.
abstract: Modification of glycoproteins by the attachment of fucose residues is widely distributed in nature. The importance of fucosylation has recently been underlined by identification of the monogenetic inherited human disease "congenital disorder of glycosylation IIc," also termed "leukocyte adhesion deficiency II." Due to defective Golgi GDP-fucose transporter (SLC35C1) activity, patients show a hypofucosylation of glycoproteins and present clinically with mental and growth retardation, persistent leukocytosis, and severe infections. To investigate effects induced by the loss of fucosylated structures in different organs, we generated a mouse model for the disease by inactivating the Golgi GDP-transporter gene (Slc35c1). Lectin binding studies revealed a tremendous reduction of fucosylated glycoconjugates in tissues and isolated cells from Slc35c1(-/-) mice. Fucose treatment of cells from different organs led to partial normalization of the fucosylation state of glycoproteins, thereby indicating an alternative GDP-fucose transport mechanism. Slc35c1-deficient mice presented with severe growth retardation, elevated postnatal mortality rate, dilatation of lung alveoles, and hypocellular lymph nodes. In vitro and in vivo leukocyte adhesion and rolling assays revealed a severe impairment of P-, E-, and L-selectin ligand function. The diversity of these phenotypic aspects demonstrates the broad general impact of fucosylation in the mammalian organism.
authors.affiliation: Department of Pediatrics, Division of Inborn Metabolic Diseases, Section of Neonatology, University Children's Hospital, Im Neuenheimer Feld 153, 69120 Heidelberg, Germany.
authors.forename: Christina C
authors.initials: CC
authors.lastname: Hellbusch
authors.forename: Markus
authors.initials: M
authors.lastname: Sperandio
authors.forename: David
authors.initials: D
authors.lastname: Frommhold
authors.forename: Sviatlana
authors.initials: S
authors.lastname: Yakubenia
authors.forename: Martin K
authors.initials: MK
authors.lastname: Wild
authors.forename: Diana
authors.initials: D
authors.lastname: Popovici
authors.forename: Dietmar
authors.initials: D
authors.lastname: Vestweber
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
authors.forename: Kurt
authors.initials: K
authors.lastname: von Figura
authors.forename: Torben
authors.initials: T
authors.lastname: Lübke
authors.forename: Christian
authors.initials: C
authors.lastname: Körner
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism; D005643:Fucose / Q000235:genetics / Q000378:metabolism*; D006031:Glycosylation; D006056:Golgi Apparatus / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D006130:Growth Disorders / Q000201:enzymology / Q000235:genetics; D036904:Leukocyte Rolling / Q000235:genetics*; D007964:Leukocytosis / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D026901:Membrane Transport Proteins / Q000172:deficiency* / Q000378:metabolism; D008661:Metabolism, Inborn Errors / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009004:Monosaccharide Transport Proteins; D046188:Protein Modification, Translational / Q000235:genetics*
chemical_list: D015815:Cell Adhesion Molecules; D026901:Membrane Transport Proteins; D009004:Monosaccharide Transport Proteins; C520021:Slc35c1 protein, mouse; D005643:Fucose