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J. Biol. Chem., Vol. 282, Issue 14, 10762-10772, April 6, 2007

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

Christina C. Hellbusch¹, Markus Sperandio², David Frommhold, Sviatlana Yakubenia^¶3, Martin K. Wild^¶4, Diana Popovici, Dietmar Vestweber^¶2, Hermann-Josef Gröne^||, Kurt von Figura^**, Torben Lübke^**, and Christian Körner⁵

From the Department of Pediatrics, Division of Inborn Metabolic Diseases and Department of Pediatrics, Section of Neonatology, University Children's Hospital, Im Neuenheimer Feld 153, 69120 Heidelberg, Germany, the ^¶Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 16, 48149 Münster, Germany, the ^||Department of Cellular and Molecular Pathology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany, and ^**Zentrum Biochemie und Molekulare Zellbiologie, Abteilung Biochemie II, University of Göttingen, Heinrich-Düker-Weg 12, 37073 Göttingen, Germany

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.

Received for publication, January 11, 2007

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by a Ph.D. fellowship from the Ev. Studienwerk Villigst e.V.

² Supported by a Deutsche Forschungsgemeinschaft Grant SP621/3-1.

³ Supported by Deutsche Forschungsgemeinschaft Grant SFB 293 and by the Max Planck Society.

⁴ Supported by International Graduate Research School "Molecular Basis of Dynamic Cell Processes," Fellowship GRK 1050.

⁵ To whom correspondence should be addressed. Tel.: 49-6221-56-39993; Fax: 49-6221-56-5565; E-mail: christian.koerner{at}med.uni-heidelberg.de.

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