Human Molecular Genetics Advance Access originally published online on August 18, 2009
Human Molecular Genetics 2009 18(22):4350-4356; doi:10.1093/hmg/ddp389
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Deficiency in COG5 causes a moderate form of congenital disorders of glycosylation
1 University Children's Hospital Zurich, Zurich, Switzerland, 2 Institute of Physiology, University of Zurich, Zurich, Switzerland, 3 Center for Human Genetics, University of Leuven, Leuven, Belgium and 4 Department of Neuropediatry, Kantonsspital Aarau, Switzerland
* To whom correspondence should be addressed at: University Children's Hospital, Division of Metabolism, Steinwiesstrasse 75, CH-8032 Zurich, Switzerland. Tel: +41 442667174; Email: patricie.paesold{at}kispi.uzh.ch
Received June 30, 2009; Accepted August 13, 2009
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.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.