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Congenital disorder of glycosylation IIc (CDG IIc), also termed leukocyte adhesion deficiency II, is a recessive syndrome characterized by slowed growth, mental retardation, and severe immunodeficiency. Recently, the gene responsible for CDG IIc was found to encode a GDP-fucose transporter. Here, we investigated the possible cause of the developmental defects in CDG IIc patients by using aDrosophila model. Biochemically, we demonstrated that aDrosophila homolog of the GDP-fucose transporter, the Golgi GDP-fucose transporter (Gfr ), specifically transports GDP-fucosein vitro . To understand the function of theGfr gene, we generated null mutants ofGfr inDrosophila . The phenotypes of theDrosophila Gfr mutants were rescued by the human GDP-fucose transporter transgene. Our phenotype analyses revealed that Notch (N) signaling was deficient in theseGfr mutants. GDP-fucose is known to be essential for the fucosylation ofN -linked glycans and forO -fucosylation, and both fucose modifications are present on N. Our results suggest that Gfr is involved in the fucosylation ofN -linked glycans on N and itsO -fucosylation, as well as those of bulk proteins. However, despite the essential role of NO -fucosylation during development, theGfr homozygote was viable. Thus, our results also indicate that theDrosophila genome encodes at least another GDP-fucose transporter that is involved in theO -fucosylation of N. Finally, we found that mammalianGfr is required for N signaling in mammalian cultured cells. Therefore, our results implicate reduced N signaling in the pathology of CDG IIc.

Notch deficiency implicated in the pathogenesis of congenital disorder of glycosylation IIc