Human RFT1 deficiency leads to a disorder of N-linked glycosylation

被引:43
|
作者
Haeuptle, Micha A. [1 ,2 ]
Pujol, Francois M. [3 ,4 ]
Neupert, Christine [6 ]
Winchester, Bryan [5 ]
Kastaniotis, Alexander J. [3 ,4 ]
Aebi, Markus [6 ]
Hennet, Thierry [1 ,2 ]
机构
[1] Univ Zurich, Inst Physiol, CH-8057 Zurich, Switzerland
[2] Univ Zurich, Zurich Ctr Integrat Human Physiol, CH-8057 Zurich, Switzerland
[3] Univ Oulu, Bioctr Oulu, FIN-90014 Oulu, Finland
[4] Univ Oulu, Dept Biochem, FIN-90014 Oulu, Finland
[5] UCL, Inst Child Hlth, Biochem Res Grp, London WC1N 1EH, England
[6] Swiss Fed Inst Technol, Inst Microbiol, CH-8093 Zurich, Switzerland
基金
芬兰科学院;
关键词
D O I
10.1016/j.ajhg.2007.12.021
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
N-linked glycosylation is an essential posttranslational modification of proteins in eukaryotes. The substrate of N-linked glycosylation, dolichol pyrophosphate (DolPP)-GlcNAc(2)Man(9)Glc(3), is assembled through a complex series of ordered reactions requiring the translocation of the intermediate DolPP-GlcNAc(2)Man(5) structure across the endoplasmic-reticulum membrane. A young patient diagnosed with a congenital disorder of glycosylation characterized by an intracellular accumulation of DolPP-G1cNAc(2)Man(5) was found to carry a homozygous point mutation in the RFT1 gene. The c.199C -> T mutation introduced the amino acid substitution p.R67C. The human RFT1 protein shares 22% identity with its yeast ortholog, which is involved in the translocation of DolPP-GlcNAc(2)Man(5) from the cytosolic into the lumenal side of the endoplasmic reticulum. Despite the low sequence similarity between the yeast and the human RFT1 proteins, we demonstrated both their functional orthology and the pathologic effect of the human p.R67C mutation by complementation assay in Delta rft1 yeast cells. The causality of the RFT1 p.R67C mutation was further established by restoration of normal glycosylation profiles in patient-derived fibroblasts after lentiviral expression of a normal RFT1 cDNA. The definition of the RFT1 defect establishes the functional conservation of the DolPP-GlcNAc(2)Man(5) translocation process in eukaryotes. RFTI deficiency in both yeast and human cells leads to the accumulation of incomplete DolPP-GlcNAc(2)Man(5) and to a profound glycosylation disorder in humans.
引用
收藏
页码:600 / 606
页数:7
相关论文
共 50 条
  • [21] Role of N-linked glycosylation on the function and expression of the human secretin receptor
    Pang, RTK
    Ng, SSM
    Cheng, CHK
    Holtmann, MH
    Miller, LJ
    Chow, BKC
    ENDOCRINOLOGY, 1999, 140 (11) : 5102 - 5111
  • [22] IDENTIFICATION OF A HUMAN GASTRIC MUCIN PRECURSOR - N-LINKED GLYCOSYLATION AND OLIGOMERIZATION
    KLOMP, LWJ
    VANRENS, L
    STROUS, GJ
    BIOCHEMICAL JOURNAL, 1994, 304 : 693 - 698
  • [23] Does Rft1 flip an N-glycan lipid precursor?
    Frank, Christian G.
    Sanyal, Sumana
    Rush, Jeffrey S.
    Waechter, Charles J.
    Menon, Anant K.
    NATURE, 2008, 454 (7204) : E3 - E4
  • [24] Cytoplasmic stress: A regulator of N-linked glycosylation
    Shang, J
    Lehrman, MA
    GLYCOBIOLOGY, 2002, 12 (10) : 679 - 679
  • [25] N-Linked Protein Glycosylation in the Endoplasmic Reticulum
    Breitling, Joerg
    Aebi, Markus
    COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY, 2013, 5 (08):
  • [26] N-linked glycosylation and homeostasis of the endoplasmic reticulum
    Cherepanova, Natalia
    Shrimal, Shiteshu
    Gilmore, Reid
    CURRENT OPINION IN CELL BIOLOGY, 2016, 41 : 57 - 65
  • [27] Dynamic graph modelling for N-linked glycosylation
    Yang D.-W.
    Wang J.
    Zhou J.-L.
    Wu H.-Y.
    Jin Q.-B.
    Wang, Jing (jwang@mail.buct.edu.cn), 2017, South China University of Technology (34): : 627 - 636
  • [28] Effects of N-linked glycosylation on the creatine transporter
    Straumann, N
    Wind, A
    Leuenberger, T
    Wallimann, T
    BIOCHEMICAL JOURNAL, 2006, 393 (02) : 459 - 469
  • [29] N-LINKED GLYCOSYLATION INFLUENCES THE THERMOSTABILITY OF RENIN
    LADENHEIM, RG
    ROUGEON, F
    COMPTES RENDUS DE L ACADEMIE DES SCIENCES SERIE III-SCIENCES DE LA VIE-LIFE SCIENCES, 1993, 316 (04): : 334 - 336
  • [30] Redox Control of N-linked Protein Glycosylation
    Petkovich, Daniel Adam
    Fomenko, Dmitri
    FASEB JOURNAL, 2013, 27