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

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

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: skmoch@lf1.cuni.cz.
  • 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: william.sessa@yale.edu.
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.

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