کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2811849 1569288 2008 7 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Human RFT1 Deficiency Leads to a Disorder of N-Linked Glycosylation
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی ژنتیک
پیش نمایش صفحه اول مقاله
Human RFT1 Deficiency Leads to a Disorder of N-Linked Glycosylation
چکیده انگلیسی

N-linked glycosylation is an essential posttranslational modification of proteins in eukaryotes. The substrate of N-linked glycosylation, dolichol pyrophosphate (DolPP)-GlcNAc2Man9Glc3, is assembled through a complex series of ordered reactions requiring the translocation of the intermediate DolPP-GlcNAc2Man5 structure across the endoplasmic-reticulum membrane. A young patient diagnosed with a congenital disorder of glycosylation characterized by an intracellular accumulation of DolPP-GlcNAc2Man5 was found to carry a homozygous point mutation in the RFT1 gene. The c.199C→T mutation introduced the amino acid substitution p.R67C. The human RFT1 protein shares 22% identity with its yeast ortholog, which is involved in the translocation of DolPP-GlcNAc2Man5 from the cytosolic into the lumenal side of the endoplasmic reticulum. Despite the low sequence similarity between the yeast and the human RFT1 proteins, we demonstrated both their functional orthology and the pathologic effect of the human p.R67C mutation by complementation assay in Δrft1 yeast cells. The causality of the RFT1 p.R67C mutation was further established by restoration of normal glycosylation profiles in patient-derived fibroblasts after lentiviral expression of a normal RFT1 cDNA. The definition of the RFT1 defect establishes the functional conservation of the DolPP-GlcNAc2Man5 translocation process in eukaryotes. RFT1 deficiency in both yeast and human cells leads to the accumulation of incomplete DolPP-GlcNAc2Man5 and to a profound glycosylation disorder in humans.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: - Volume 82, Issue 3, 3 March 2008, Pages 600–606
نویسندگان
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