In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 102, No. 51 ( 2005-12-20), p. 18532-18537
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.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.0504115102
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2005
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
Permalink
