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

Christina C Hellbusch,Markus Sperandio,David Frommhold,Sviatlana Yakubenia,Martin K Wild,Diana Popovici,Dietmar Vestweber,Hermann-Josef Gröne,Kurt Von Figura,Torben Lübke,Christian Körner

doi:10.1074/jbc.m700314200

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.

Highlights

Chemical properties and the function of proteins in a variety of biological processes, including folding, solubility, sorting, proteolytic stability, and receptor-ligand interactions
Fucosylation and Function of Selectin Ligands on Leukocytes— Since it is known from CDG-IIc patients that leukocyte rolling is severely affected due to the loss of fucose residues linked to sialyl Lewis X, an important binding partner for selectins, we studied fucosylation and function of these ligands
Binding of fucose residues to glycoconjugates plays a crucial role in many intra- and intercellular recognition processes and interactions as well as in signal transduction pathways [45]

Summary

Introduction

Chemical properties and the function of proteins in a variety of biological processes, including folding, solubility, sorting, proteolytic stability, and receptor-ligand interactions. Histological Abnormalities in Lymph Nodes and Lungs of Slc35c1Ϫ/Ϫ Mice—Organs of Slc35c1-deficient mice were proportionally smaller as compared with age-matched controls but showed no significant abnormalities concerning cellularity and architecture in histological sections stained with hematoxylin/

Results

Conclusion