title: Deficiency in COG5 causes a moderate form of congenital disorders of glycosylation.
abstract: The conserved oligomeric Golgi (COG) complex is a tethering factor composed of eight subunits that is involved in the retrograde transport of intra-Golgi components. Deficient biosynthesis of COG subunits leads to alterations of protein trafficking along the secretory pathway and thereby to severe diseases in humans. Since the COG complex affects the localization of several Golgi glycosyltransferase enzymes, COG deficiency also leads to defective protein glycosylation, thereby explaining the classification of COG deficiencies as forms of congenital disorders of glycosylation (CDG). To date, mutations in COG1, COG4, COG7 and COG8 genes have been associated with diseases, which range from severe multi-organ disorders to moderate forms of neurological impairment. In the present study, we describe a new type of COG deficiency related to a splicing mutation in the COG5 gene. Sequence analysis in the patient identified a homozygous intronic substitution (c.1669-15T>C) leading to exon skipping and severely reduced expression of the COG5 protein. This defect was associated with a mild psychomotor retardation with delayed motor and language development. Analysis of different serum glycoproteins revealed a CDG phenotype with typical undersialylation of N- and O-glycans. Retrograde Golgi-to-endoplasmic reticulum trafficking was markedly delayed in the patient's fibroblast upon brefeldin-A treatment, which is a hallmark of COG deficiency. This trafficking delay could be restored to normal values by expressing a wild-type COG5 cDNA in the patient cells. This case demonstrates that COG deficiency and thereby CDG must be taken into consideration even in children presenting mild neurological impairments.
authors.affiliation: University Children's Hospital Zurich, Division of Metabolism, Zurich, Switzerland. patricie.paesold@kispi.uzh.ch
authors.forename: Patricie
authors.initials: P
authors.lastname: Paesold-Burda
authors.forename: Charlotte
authors.initials: C
authors.lastname: Maag
authors.forename: Heinz
authors.initials: H
authors.lastname: Troxler
authors.forename: François
authors.initials: F
authors.lastname: Foulquier
authors.forename: Peter
authors.initials: P
authors.lastname: Kleinert
authors.forename: Siegrun
authors.initials: S
authors.lastname: Schnabel
authors.forename: Matthias
authors.initials: M
authors.lastname: Baumgartner
authors.forename: Thierry
authors.initials: T
authors.lastname: Hennet
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency* / Q000235:genetics; D000293:Adolescent; D002478:Cells, Cultured; D002648:Child; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D008661:Metabolism, Inborn Errors / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D012326:RNA Splicing
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; C115632:COG5 protein, human