title: A new inborn error of glycosylation due to a Cog8 deficiency reveals a critical role for the Cog1-Cog8 interaction in COG complex formation.
abstract: 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).
authors.affiliation: Laboratory for Molecular Diagnostics, Center for Human Genetics, University of Leuven, Herestraat 49, B-3000 Leuven, Belgium.
authors.forename: François
authors.initials: F
authors.lastname: Foulquier
authors.forename: Daniel
authors.initials: D
authors.lastname: Ungar
authors.forename: Ellen
authors.initials: E
authors.lastname: Reynders
authors.forename: Renate
authors.initials: R
authors.lastname: Zeevaert
authors.forename: Philippa
authors.initials: P
authors.lastname: Mills
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: García-Silva
authors.forename: Paz
authors.initials: P
authors.lastname: Briones
authors.forename: Bryan
authors.initials: B
authors.lastname: Winchester
authors.forename: Willy
authors.initials: W
authors.lastname: Morelle
authors.forename: Monty
authors.initials: M
authors.lastname: Krieger
authors.forename: Willem
authors.initials: W
authors.lastname: Annaert
authors.forename: Gert
authors.initials: G
authors.lastname: Matthijs
mesh_terms: 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
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; C486489:COG1 protein, human; D018389:Codon, Nonsense; D006023:Glycoproteins; D011134:Polysaccharides; C090202:COG2 protein, human; D020126:Brefeldin A