title: Notch deficiency implicated in the pathogenesis of congenital disorder of glycosylation IIc.
abstract: 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 a Drosophila model. Biochemically, we demonstrated that a Drosophila homolog of the GDP-fucose transporter, the Golgi GDP-fucose transporter (Gfr), specifically transports GDP-fucose in vitro. To understand the function of the Gfr gene, we generated null mutants of Gfr in Drosophila. The phenotypes of the Drosophila Gfr mutants were rescued by the human GDP-fucose transporter transgene. Our phenotype analyses revealed that Notch (N) signaling was deficient in these Gfr mutants. GDP-fucose is known to be essential for the fucosylation of N-linked glycans and for O-fucosylation, and both fucose modifications are present on N. Our results suggest that Gfr is involved in the fucosylation of N-linked glycans on N and its O-fucosylation, as well as those of bulk proteins. However, despite the essential role of N O-fucosylation during development, the Gfr homozygote was viable. Thus, our results also indicate that the Drosophila genome encodes at least another GDP-fucose transporter that is involved in the O-fucosylation of N. Finally, we found that mammalian Gfr is required for N signaling in mammalian cultured cells. Therefore, our results implicate reduced N signaling in the pathology of CDG IIc.
authors.affiliation: Genome and Drug Research Center, Tokyo University of Science, Noda, Chiba 278-8510, Japan.
authors.forename: Hiroyuki O
authors.initials: HO
authors.lastname: Ishikawa
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Higashi
authors.forename: Tomonori
authors.initials: T
authors.lastname: Ayukawa
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sasamura
authors.forename: Motoo
authors.initials: M
authors.lastname: Kitagawa
authors.forename: Kenichi
authors.initials: K
authors.lastname: Harigaya
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Aoki
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Ishida
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Sanai
authors.forename: Kenji
authors.initials: K
authors.lastname: Matsuno
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D029721:Drosophila Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism*; D005643:Fucose / Q000378:metabolism; D006031:Glycosylation; D006056:Golgi Apparatus / Q000378:metabolism; D006154:Guanosine Diphosphate Fucose / Q000378:metabolism; D006801:Humans; D018370:Leukocyte-Adhesion Deficiency Syndrome / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D009004:Monosaccharide Transport Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D051880:Receptors, Notch / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D029721:Drosophila Proteins; D008024:Ligands; D009004:Monosaccharide Transport Proteins; C497759:N protein, Drosophila; D051880:Receptors, Notch; C494581:nac protein, Drosophila; D006154:Guanosine Diphosphate Fucose; D005643:Fucose