Mutation of Nogo-B Receptor, a Subunit of cis-Prenyltransferase, Causes a Congenital Disorder of Glycosylation

• DOI: 10.1016/j.cmet.2014.06.016
• Publication Date: 2014-07-24T15:51:50Z
• 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
• Keywords: Male; 0303 health sciences; Glycosylation; Saccharomyces cerevisiae Proteins; Physiology; Molecular Sequence Data; Receptors, Cell Surface; Cell Biology; Saccharomyces cerevisiae; Evolution, Molecular; Gene Knockout Techniques; Mice; 03 medical and health sciences; Metabolic Diseases; Transferases; Dolichols; Animals; Humans; Point Mutation; Female; Amino Acid Sequence; Molecular Biology; Cells, Cultured

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.