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.

Bascom Palmer Eye Institute University of Miami Miller School of Medicine 900 NW 17th Street Miami FL 33136 USA

Department of Biochemistry Duke University Medical Center DUMC 2927 Durham NC 27710 USA

Department of Pediatrics 1st Faculty of Medicine Charles University and General University Hospital Ke Karlovu 2 Prague 2 128 08 Czech Republic

Department of Pharmacology and Vascular Biology and Therapeutics Program Yale University School of Medicine 10 Amistad Street New Haven CT 06520 USA

Institute for Inherited Metabolic Disorders 1st Faculty of Medicine Charles University and General University Hospital Ke Karlovu 2 Prague 2 128 08 Czech Republic

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