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

  • Cell Metab. 2014 Sep 2;20(3):448-57. doi: 10.1016/j.cmet.2014.06.016.
Eon Joo Park  1 ,  Kariona A Grabińska  1 ,  Ziqiang Guan  2 ,  Viktor Stránecký  3 ,  Hana Hartmannová  3 ,  Kateřina Hodaňová  3 ,  Veronika Barešová  3 ,  Jana Sovová  3 ,  Levente Jozsef  1 ,  Nina Ondrušková  4 ,  Hana Hansíková  4 ,  Tomáš Honzík  4 ,  Jiří Zeman  4 ,  Helena Hůlková  3 ,  Rong Wen  5 ,  Stanislav Kmoch  6 ,  William C Sessa  7
Affiliations
  • 1. Department of Pharmacology and Vascular Biology and Therapeutics Program, Yale University School of Medicine, 10 Amistad Street, New Haven, CT 06520, USA.
  • 2. Department of Biochemistry, Duke University Medical Center, DUMC 2927, Durham, NC 27710, USA.
  • 3. Institute for Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Ke Karlovu 2, Prague 2, 128 08 Czech Republic.
  • 4. Department of Pediatrics, First Faculty of Medicine, Charles University and General University Hospital, Ke Karlovu 2, Prague 2, 128 08 Czech Republic.
  • 5. Bascom Palmer Eye Institute, University of Miami, Miller School of Medicine, 900 NW 17th Street, Miami, FL 33136, USA.
  • 6. 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: [email protected].
  • 7. Department of Pharmacology and Vascular Biology and Therapeutics Program, Yale University School of Medicine, 10 Amistad Street, New Haven, CT 06520, USA. Electronic address: [email protected].
PMID: 25066056 DOI: 10.1016/j.cmet.2014.06.016
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.