Mutation of Nogo-B receptor, a subunit of cis-prenyltransferase, causes a congenital disorder of glycosylation.

Abstract

Dolichol is an obligate carrier of glycans for N-linked protein glycosylation, O-mannosylation, and GPI anchor biosynthesis. cis-prenyltransferase (cis-PTase) is the first enzyme committed to the synthesis of dolichol. However, the proteins responsible for mammalian cis-PTase activity have not been delineated. Here we show that Nogo-B receptor (NgBR) is a subunit required for dolichol synthesis in yeast, mice, and man. Moreover, we describe a family with a congenital disorder of glycosylation caused by a loss of function mutation in the conserved C terminus of NgBR-R290H and show that fibroblasts isolated from patients exhibit reduced dolichol profiles and enhanced accumulation of free cholesterol identically to fibroblasts from mice lacking NgBR. Mutation of NgBR-R290H in man and orthologs in yeast proves the importance of this evolutionarily conserved residue for mammalian cis-PTase activity and function. Thus, these data provide a genetic basis for the essential role of NgBR in dolichol synthesis and protein glycosylation.

• Authors: Eon Joo Park, Kariona A Grabińska, Ziqiang Guan, Viktor Stránecký, Hana Hartmannová, Kateřina Hodaňová, Veronika Barešová, Jana Sovová, Levente Jozsef, Nina Ondrušková, Hana Hansíková, Tomáš Honzík, Jiří Zeman, Helena Hůlková, Rong Wen, Stanislav Kmoch, William C Sessa
• Journal: Cell metabolism (Cell Metab) Vol. 20 Issue 3 Pg. 448-57 (Sep 02 2014) ISSN: 1932-7420 [Electronic] United States
• PMID: 25066056 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Dolichols
• NUS1 protein, human
• Nogo-B receptor, mouse
• Receptors, Cell Surface
• Saccharomyces cerevisiae Proteins
• Transferases
• cis-prenyl transferase

Topics

• Amino Acid Sequence
• Animals
• Cells, Cultured
• Dolichols (metabolism)
• Evolution, Molecular
• Female
• Gene Knockout Techniques
• Glycosylation
• Humans
• Male
• Metabolic Diseases (genetics, metabolism)
• Mice
• Molecular Sequence Data
• Point Mutation
• Receptors, Cell Surface (chemistry, genetics, metabolism)
• Saccharomyces cerevisiae (chemistry, genetics, metabolism)
• Saccharomyces cerevisiae Proteins (chemistry, genetics, metabolism)
• Transferases (chemistry, genetics, metabolism)