title: Fatal outcome due to deficiency of subunit 6 of the conserved oligomeric Golgi complex leading to a new type of congenital disorders of glycosylation.
abstract: Deficiency of subunit 6 of the conserved oligomeric Golgi (COG6) complex causes a new combined N- and O-glycosylation deficiency of the congenital disorders of glycosylation, designated as CDG-IIL (COG6-CDG). The index patient presented with a severe neurologic disease characterized by vitamin K deficiency, vomiting, intractable focal seizures, intracranial bleedings and fatal outcome in early infancy. Analysis of oligosaccharides from serum transferrin by HPLC and mass spectrometry revealed the loss of galactose and sialic acid residues, whereas import and transfer of these sugar residues into Golgi-enriched vesicles or onto proteins, respectively, were normal to slightly reduced. Western blot examinations combined with gel filtration chromatography studies in patient-derived skin fibroblasts showed a severely reduced expression of the mentioned subunit and the occurrence of COG complex fragments at the expense of the integral COG complex. Sequencing of COG6-cDNA and COG6 gene resulted in a homozygous mutation (c.G1646T), leading to amino acid exchange p.G549V in the COG6 protein. Retroviral complementation of the patients' fibroblasts with the wild-type COG6-cDNA led to normalization of the COG complex-depending retrograde protein transport after Brefeldin A treatment, demonstrated by immunofluorescence analysis.
authors.affiliation: Center for Child and Adolescent Medicine, Center for Metabolic Diseases Heidelberg, Department I, Heidelberg, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Lübbehusen
authors.forename: Christian
authors.initials: C
authors.lastname: Thiel
authors.forename: Nina
authors.initials: N
authors.lastname: Rind
authors.forename: Daniel
authors.initials: D
authors.lastname: Ungar
authors.forename: Berthil H C M T
authors.initials: BH
authors.lastname: Prinsen
authors.forename: Tom J
authors.initials: TJ
authors.lastname: de Koning
authors.forename: Peter M
authors.initials: PM
authors.lastname: van Hasselt
authors.forename: Christian
authors.initials: C
authors.lastname: Körner
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency* / Q000235:genetics; D002478:Cells, Cultured; D018981:Congenital Disorders of Glycosylation / Q000235:genetics / Q000378:metabolism*; D017809:Fatal Outcome; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D007223:Infant; D020125:Mutation, Missense; D021381:Protein Transport
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; C553748:COG6 protein, human