title: The Drosophila neurally altered carbohydrate mutant has a defective Golgi GDP-fucose transporter.
abstract: Studying genetic disorders in model organisms can provide insights into heritable human diseases. The Drosophila neurally altered carbohydrate (nac) mutant is deficient for neural expression of the HRP epitope, which consists of N-glycans with core α1,3-linked fucose residues. Here, we show that a conserved serine residue in the Golgi GDP-fucose transporter (GFR) is substituted by leucine in nac(1) flies, which abolishes GDP-fucose transport in vivo and in vitro. This loss of function is due to a biochemical defect, not to destabilization or mistargeting of the mutant GFR protein. Mass spectrometry and HPLC analysis showed that nac(1) mutants lack not only core α1,3-linked, but also core α1,6-linked fucose residues on their N-glycans. Thus, the nac(1) Gfr mutation produces a previously unrecognized general defect in N-glycan core fucosylation. Transgenic expression of a wild-type Gfr gene restored the HRP epitope in neural tissues, directly demonstrating that the Gfr mutation is solely responsible for the neural HRP epitope deficiency in the nac(1) mutant. These results validate the Drosophila nac(1) mutant as a model for the human congenital disorder of glycosylation, CDG-IIc (also known as LAD-II), which is also the result of a GFR deficiency.
authors: Department of Molecular Biology, University of Wyoming, Laramie, WY 82071, USA.
authors: Christoph
authors: C
authors: Geisler
authors: Varshika
authors: V
authors: Kotu
authors: Mary
authors: M
authors: Sharrow
authors: Dubravko
authors: D
authors: Rendić
authors: Gerald
authors: G
authors: Pöltl
authors: Michael
authors: M
authors: Tiemeyer
authors: Iain B H
authors: IB
authors: Wilson
authors: Donald L
authors: DL
authors: Jarvis
mesh_terms: D000818:Animals; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D000939:Epitopes / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006031:Glycosylation; D006056:Golgi Apparatus / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009004:Monosaccharide Transport Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009417:Nerve Tissue / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000235:genetics
chemical_list: D029721:Drosophila Proteins; D000939:Epitopes; D009004:Monosaccharide Transport Proteins; D009419:Nerve Tissue Proteins; C494581:nac protein, Drosophila