The gene defective in leukocyte adhesion deficiency II encodes a putative GDP-fucose transporter

Leukocyte adhesion deficiency II(LAD II) is characterized by the lack of fu cosylated glycoconjugates, including selectin ligands, causing immunodefici ency and severe mental and growth retardation(1-3) No deficiency in fucosyl transferase activities(2,4) or in the activities of enzymes involved in GDP -fucose biosynthesis(5) has been found. Instead, the transport of GDP-fucos e into isolated Golgi vesicles of LAD II cells appeared to be reduced(6). T o identify the gene mutated in LAD II, we cloned 12 cDNAs from Caenorhabdit is 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 f ucosylated glycoconjugates with high efficiency and allowed us to identify a human homolog with 55% identity, which also directed re-expression of fuc osylated glycoconjugates, Both proteins were localized to the Golgi, The co rresponding endogenous protein in LAD II cells had an R147C amino acid chan ge in the conserved fourth transmembrane region. Overexpression of this mut ant protein in cells from a patient with LAD did not rescue fucosylation, d emonstrating that the point mutation affected the activity of the protein. Thus, we have identified the first putative CDP fucose transporter, which h as been highly conserved throughout evolution. A point mutation in its gene is responsible for the disease in this patient with LAD II.