Minireview Deficiencies in subunits of the Conserved Oligomeric Golgi (COG) complex define a novel group of Congenital Disorders of Glycosylation Renate Zeevaert a,b , Franc¸ois Foulquier a , Jaak Jaeken b, * , Gert Matthijs a a Center for Human Genetics, University Hospital Gasthuisberg, Herestraat 49, B3000 Leuven, Belgium b Department of Pediatrics, University Hospital Gasthuisberg, Herestraat 49, B3000 Leuven, Belgium Received 17 July 2007; received in revised form 16 August 2007; accepted 16 August 2007 Available online 29 September 2007 Abstract Processing of the glycan structures on glycoproteins by different glycosylation enzymes depends on, among other, the non-uniform distribution of these enzymes within the Golgi stacks. This compartmentalization is achieved by a balance between anterograde and ret- rograde vesicular trafficking. If the balance is disturbed, the glycosylation machinery is mislocalized, which can cause Congenital Dis- orders of Glycosylation type II (CDG-II), as illustrated by the identification of congenital defects in the Conserved Oligomeric Golgi (COG) complex in humans. We collected findings from different COG deficient cell types, such as CHO, yeast and human fibroblasts to hypothesize about structure and function of the COG complex, and compared the phenotypes and genotypes of the patients known with a COG deficiency. Among 35 CDG-II patients we found 5 patients with a COG defect. COG defects are a novel group of CDG-II with deficient N- as well as O-glycosylation. Ó 2007 Elsevier Inc. All rights reserved. Keywords: CDG; COG complex; Glycosylation; Vesicular trafficking Introduction The endoplasmic reticulum (ER) and Golgi apparatus are crucial organelles in the secretory pathway of proteins. Newly synthesized proteins enter the ER through docking of the ribosome onto a protein pore of the ER membrane [1]. Proteins are then transported from ER to Golgi and from Golgi to endosomes, lysosomes or the plasma mem- brane by transport vesicles [2]. During this process, a set of post-translational modifications like glycosylation, tyro- sine sulfation, lysosomal targeting of enzymes and multi- mer assembly occur in the Golgi apparatus [3–5]. The covalent attachment of a glycan onto a protein con- stitutes the glycosylation process, an important post-trans- lational modification involved in folding, stability and interactions of glycoproteins [6–8]. Glycosylation can be subdivided into N-, O- and C-glycosylation: N-glycans are attached to an amino-group of asparagines [9], O-gly- cans to the hydroxyl group of serine and/or threonine [6] and C-glycans to the C-2 atom of the indole moiety of tryp- tophan [10]. N-Glycosylation starts in the endoplasmic reticulum (ER) with the assembly of a dolichol-linked oligosaccha- ride consisting of 14 monosaccharides (3 glucoses, 9 man- noses and 2 N-acetylglucosamines). During assembly, the growing oligosaccharide is ‘‘flipped’’ from the cytoplasmic side of the ER to its luminal side where the last four man- noses and three glucoses are added. The resulting oligosac- charide is then transferred from its lipid carrier to a nascent protein in the ER lumen. Further processing in ER and Golgi by glycosidases and glycosyltransferases results in a mature complex type N-glycan [9]. O-Glycosylation on the other hand, mostly takes place in the Golgi apparatus and consists only of assembly with- out processing. A monosaccharide is transferred directly onto a serine or a threonine. The first monosaccharide can be N-acetylgalactosamine in case of a mucin type 1096-7192/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.ymgme.2007.08.118 * Corresponding author. Fax: +32 16 343842. E-mail address: Jaak.Jaeken@uz.kuleuven.be (J. Jaeken). www.elsevier.com/locate/ymgme Molecular Genetics and Metabolism 93 (2008) 15–21