Insights into leukocyte adhesion deficiency type 2 from a novel mutation in the GDP-fucose transporter gene

Hidalgo, Andrés; Ma, Songhui; Peired, Anna Julie; Weiss, Linnea A.; Cunningham‐Rundles, Charlotte; Frenette, Paul S.

doi:10.1182/blood-2002-09-2840

Cited by 92 publications

(88 citation statements)

References 32 publications

(47 reference statements)

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“…This rare disorder is characterized by marked leukocytosis and recurrent bacterial infections without pus formation. 94 Similarly, mice lacking specific fucosyltransferases (IV and VII) have the same deficits in neutrophil adhesion as those found in selectin-deficient mice. 95,96 Despite the known importance of fucosylation in PMN extravasation, the role of fucosylated glycans during PMN epithelial interactions and PMN function in general have not been characterized to date.…”

Section: Neutrophil-epithelial Interactionsmentioning

confidence: 89%

Neutrophil-Epithelial Interactions

Parkos

2016

The American Journal of Pathology

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Section: Neutrophil-epithelial Interactionsmentioning

confidence: 89%

Neutrophil-Epithelial Interactions

Parkos

2016

The American Journal of Pathology

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“…Despite the fact that the molecular defect of CDG-IIc has been found, the general relevance of the loss of fucosylation in CDG-IIc patients remains mainly elusive. This is also true for the molecular mechanisms enabling the successful treatment of patient-derived fibroblasts as well as CDG-IIc patients by fucose supplementation (10,14,15). To improve the understanding of the pathogenesis of CDG-IIc and get new insights into the functional role of fucosylation in mammals, we generated mice with a null mutation of the murine ortholog of the human SLC35C1 gene.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, therapeutic use of a high fucose diet led to a significant improvement in selectin ligand function and restored normal white blood cell counts in some of the CDG-IIc patients (14,15). However, it has not been shown if normalization of fucose incorporation by treatment with exogenous L-fucose is dependent on a residual activity of SLC35C1 or whether it is mediated by an alternative GDP-fucose transport system.…”

Section: The Fucosylation Defect In Primary Mammalian Cells Deficientmentioning

confidence: 99%

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Golgi GDP-fucose Transporter-deficient Mice Mimic Congenital Disorder of Glycosylation IIc/Leukocyte Adhesion Deficiency II

Hellbusch

Sperandio

Frommhold

et al. 2007

Journal of Biological Chemistry

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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.The covalent attachment of oligosaccharide moieties to newly synthesized proteins comprises one of the most frequent but also complex forms of co-and posttranslational protein modifications, which has been found in nearly all living organisms (1). Glycan structures affect the physicochemical properties and the function of proteins in a variety of biological processes, including folding, solubility, sorting, proteolytic stability, and receptor-ligand interactions. In mammalian organisms, the biosynthesis of the oligosaccharide chains requires a broad spectrum of glycosyltransferases, glycosidases, transport proteins, and 13 different monosaccharides (2-4).Due to its variability of binding types (␣-1,2-, ␣-1,3-, ␣-1,4-, and ␣-1,6-fucosylation have been described), the monosaccharide fucose plays an important role in the microheterogeneity of oligosaccharide structures (5). Fucose residues are predominantly linked to peripheral parts of N-, O-, and lipid-linked oligosaccharides, thereby building cap structures, which have been observed in many surface-localized and secreted proteins,

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“…Surprisingly, removal of Pofut1 in the 2-cell blastocyst has no consequences prior to gastrulation [39]. Interestingly, inactivation of the Golgi GDP-Fucose transporter is associated with leukocyte adhesion defects in humans [40] and in mice [41], and gives a mild, temperature-sensitive Notch phenotype in flies [42]. Transport of GDP-Fucose may also be mediated by another transporter [43].…”

Section: Abbreviationsmentioning

confidence: 99%