A new inborn error of glycosylation due to a Cog8 deficiency reveals a critical role for the Cog1-Cog8 interaction in COG complex formation.
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 beta1,4-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).
Foulquier
François
F
Laboratory for Molecular Diagnostics, Center for Human Genetics, University of Leuven, Herestraat 49, B-3000 Leuven, Belgium.
Ungar
Daniel
D
Reynders
Ellen
E
Zeevaert
Renate
R
Mills
Philippa
P
García-Silva
Maria Teresa
MT
Briones
Paz
P
Winchester
Bryan
B
Morelle
Willy
W
Krieger
Monty
M
Annaert
Willem
W
Matthijs
Gert
G
D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D020126:Brefeldin A / Q000494:pharmacology; D002239:Carbohydrate Metabolism, Inborn Errors / Q000235:genetics / Q000378:metabolism*; D002648:Child; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006031:Glycosylation; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D011134:Polysaccharides / Q000378:metabolism; D011485:Protein Binding; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014162:Transfection
D033942:Adaptor Proteins, Vesicular Transport; C486489:COG1 protein, human; D018389:Codon, Nonsense; D006023:Glycoproteins; D011134:Polysaccharides; C090202:COG2 protein, human; D020126:Brefeldin A