A new inborn error of glycosylation due to a Cog8 deficiency reveals a critical role for the Cog1-Cog8 interaction in COG complex formation

被引:97
作者
Foulquier, Francois
Ungar, Daniel
Reynders, Ellen
Zeevaert, Renate
Mills, Philippa
Garcia-Silva, Maria Teresa
Briones, Paz
Winchester, Bryan
Morelle, Willy
Krieger, Monty
Annaert, Willem
Matthijs, Gert
机构
[1] Univ Leuven, Lab Mol Diagnost, B-3000 Louvain, Belgium
[2] Univ Leuven, Lab Membrane Trafficking & VIB11, Ctr Human Genet, B-3000 Louvain, Belgium
[3] Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA
[4] UCL, Biochem Endocrinol & Metab Unit, Inst Child Hlth, London WC1N 1EH, England
[5] Hosp 12 Octubre, Dept Pediat, Unidad Enfermedades Mitocondriales Enfermedades M, E-28041 Madrid, Spain
[6] Corp Sanit Clin, Inst Clin Biochem, Barcelona 08028, Spain
[7] CSIC, E-08028 Barcelona, Spain
[8] Univ Lille 1, Lab Struct & Funct Glycobiol, UMR 8576, CNRS, F-59655 Villeneuve Dascq, France
[9] MIT, Dept Biol, Cambridge, MA 02139 USA
关键词
D O I
10.1093/hmg/ddl476
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The hetero-octameric conserved oligomeric Golgi (COG) complex is essential for the structure/function of the Golgi apparatus through regulation of membrane trafficking. Here, we describe a patient with a mild form of a congenital disorder of glycosylation type II (CDG-II), which is caused by a homozygous nonsense mutation in the hCOG8 gene. This leads to a premature stop codon resulting in a truncated Cog8 subunit lacking the 76 C-terminal amino acids. Mass spectrometric analysis of the N- and O-glycan structures identified a mild sialylation deficiency. We showed that the molecular basis of this defect in N- and O-glycosylation is caused by the disruption of the Cog1-Cog8 interaction due to truncation. As a result, Cog1 deficiency accompanies the Cog8 deficiency, preventing assembly of the intact, stable complex and resulting in the appearance of smaller subcomplexes. Moreover, levels of beta 1,4-galactosytransferase were significantly reduced. The defects in O-glycosylation could be fully restored by transfecting the patient's fibroblasts with full-length Cog8. The Cog8 defect described here represents a novel type of CDG-II, which we propose to name as CDG-IIh or CDG caused by Cog8 deficiency (CDG-II/Cog8).
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页码:717 / 730
页数:14
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