title: The gene defective in leukocyte adhesion deficiency II encodes a putative GDP-fucose transporter.
abstract: Leukocyte adhesion deficiency II (LAD II) is characterized by the lack of fucosylated glycoconjugates, including selectin ligands, causing immunodeficiency and severe mental and growth retardation. No deficiency in fucosyltransferase activities or in the activities of enzymes involved in GDP-fucose biosynthesis has been found. Instead, the transport of GDP-fucose into isolated Golgi vesicles of LAD II cells appeared to be reduced. To identify the gene mutated in LAD II, we cloned 12 cDNAs from Caenorhabditis elegans, encoding multi-spanning transmembrane proteins with homology to known nucleotide sugar transporters, and transfected them into fibroblasts from an LAD II patient. One of these clones re-established expression of fucosylated glycoconjugates with high efficiency and allowed us to identify a human homolog with 55% identity, which also directed re-expression of fucosylated glycoconjugates. Both proteins were localized to the Golgi. The corresponding endogenous protein in LAD II cells had an R147C amino acid change in the conserved fourth transmembrane region. Overexpression of this mutant protein in cells from a patient with LAD II did not rescue fucosylation, demonstrating that the point mutation affected the activity of the protein. Thus, we have identified the first putative GDP-fucose transporter, which has been highly conserved throughout evolution. A point mutation in its gene is responsible for the disease in this patient with LAD II.
authors.affiliation: Institut für Zellbiologie, ZMBE, Universität Münster, Münster, and Max-Planck-Institut für Klinische and Physiologische Forschung, Bad Nauheim, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Lühn
authors.forename: M K
authors.initials: MK
authors.lastname: Wild
authors.forename: M
authors.initials: M
authors.lastname: Eckhardt
authors.forename: R
authors.initials: R
authors.lastname: Gerardy-Schahn
authors.forename: D
authors.initials: D
authors.lastname: Vestweber
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002451:Cell Compartmentation; D005816:Genetic Complementation Test; D006031:Glycosylation; D006056:Golgi Apparatus / Q000737:chemistry; D006154:Guanosine Diphosphate Fucose / Q000378:metabolism*; D006801:Humans; D018370:Leukocyte-Adhesion Deficiency Syndrome / Q000145:classification / Q000209:etiology / Q000235:genetics*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009004:Monosaccharide Transport Proteins; D017354:Point Mutation; D017386:Sequence Homology, Amino Acid
chemical_list: D002352:Carrier Proteins; D009004:Monosaccharide Transport Proteins; C426650:SLC35C1 protein, human; D006154:Guanosine Diphosphate Fucose