title: 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: Department of Pharmacology and Vascular Biology and Therapeutics Program, Yale University School of Medicine, 10 Amistad Street, New Haven, CT 06520, USA.
authors: Eon Joo
authors: EJ
authors: Park
authors: Department of Pharmacology and Vascular Biology and Therapeutics Program, Yale University School of Medicine, 10 Amistad Street, New Haven, CT 06520, USA.
authors: Kariona A
authors: KA
authors: Grabińska
authors: Department of Biochemistry, Duke University Medical Center, DUMC 2927, Durham, NC 27710, USA.
authors: Ziqiang
authors: Z
authors: Guan
authors: Institute for Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Ke Karlovu 2, Prague 2, 128 08 Czech Republic.
authors: Viktor
authors: V
authors: Stránecký
authors: Institute for Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Ke Karlovu 2, Prague 2, 128 08 Czech Republic.
authors: Hana
authors: H
authors: Hartmannová
authors: Institute for Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Ke Karlovu 2, Prague 2, 128 08 Czech Republic.
authors: Kateřina
authors: K
authors: Hodaňová
authors: Institute for Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Ke Karlovu 2, Prague 2, 128 08 Czech Republic.
authors: Veronika
authors: V
authors: Barešová
authors: Institute for Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Ke Karlovu 2, Prague 2, 128 08 Czech Republic.
authors: Jana
authors: J
authors: Sovová
authors: Department of Pharmacology and Vascular Biology and Therapeutics Program, Yale University School of Medicine, 10 Amistad Street, New Haven, CT 06520, USA.
authors: Levente
authors: L
authors: Jozsef
authors: Department of Pediatrics, First Faculty of Medicine, Charles University and General University Hospital, Ke Karlovu 2, Prague 2, 128 08 Czech Republic.
authors: Nina
authors: N
authors: Ondrušková
authors: Department of Pediatrics, First Faculty of Medicine, Charles University and General University Hospital, Ke Karlovu 2, Prague 2, 128 08 Czech Republic.
authors: Hana
authors: H
authors: Hansíková
authors: Department of Pediatrics, First Faculty of Medicine, Charles University and General University Hospital, Ke Karlovu 2, Prague 2, 128 08 Czech Republic.
authors: Tomáš
authors: T
authors: Honzík
authors: Department of Pediatrics, First Faculty of Medicine, Charles University and General University Hospital, Ke Karlovu 2, Prague 2, 128 08 Czech Republic.
authors: Jiří
authors: J
authors: Zeman
authors: Institute for Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Ke Karlovu 2, Prague 2, 128 08 Czech Republic.
authors: Helena
authors: H
authors: Hůlková
authors: Bascom Palmer Eye Institute, University of Miami, Miller School of Medicine, 900 NW 17th Street, Miami, FL 33136, USA.
authors: Rong
authors: R
authors: Wen
authors: Institute for Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Ke Karlovu 2, Prague 2, 128 08 Czech Republic. Electronic address: skmoch@lf1.cuni.cz.
authors: Stanislav
authors: S
authors: Kmoch
authors: Department of Pharmacology and Vascular Biology and Therapeutics Program, Yale University School of Medicine, 10 Amistad Street, New Haven, CT 06520, USA. Electronic address: william.sessa@yale.edu.
authors: William C
authors: WC
authors: Sessa
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D004286:Dolichols / Q000378:metabolism; D019143:Evolution, Molecular; D005260:Female; D055786:Gene Knockout Techniques; D006031:Glycosylation; D006801:Humans; D008297:Male; D008659:Metabolic Diseases / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D017354:Point Mutation; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014166:Transferases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D004286:Dolichols; C512614:NUS1 protein, human; C512615:Nogo-B receptor, mouse; D011956:Receptors, Cell Surface; D029701:Saccharomyces cerevisiae Proteins; D014166:Transferases; C106821:cis-prenyl transferase