## 5 Gorab, a Scaffolding Protein for COPI, Is Involved in Geroderma Osteodysplastica
COG complex is evolutionarily conserved with COG subunits present in all the eukaryotic kingdom [126; 127]. The requirement for COG complex for proper glycosylation was demonstrated in model organisms and humans [106; 109; 128; 129; 130; 131; 132; 133; 134]. Several groups studied the effects of siRNA-mediated knockdown (KD) of individual COG subunits in HeLa cells in studies that complemented the analysis of patients' fibroblasts [135; 136; 137; 138; 106]. In response to depletion of COG complex subunits, the entire COG complex is non-functional and several glycosylation enzymes including _medial_- (MGAT1 and MAN2A1), and _trans_-Golgi (B4 GALT1 and ST6 GAL1)- glycosyltransferases were severely mislocalized [133; 106]. \(N\)-glycan profiling revealed decreased levels of sialylation in COG3 and COG4 KDs [133]. Another study reported defects of terminal sialylation in COG3 and COG7 KD [136]. More recently the CRISPR/Cas9 approach was used to generate HEK293T knockout cell lines missing individual COG subunits. KO cell lines displayed retrograde trafficking defects accompanied by sialylation and fucosylation alterations, albeit with effects that varied with the affected subunit [110]. The effects of COG mutations have been studied in many model organisms including yeast, worms and fruit flies, and several phenotypic effects at the cellular and organismal levels have been reported [103]. The loss of COG1 (_cog1_/LDL cells) or COG2 (_cog2_/LDL cells) in Chinese hamster ovary (CHO) cells disrupts Golgi structure, resulting in defects of protein sorting and secretion and immature of \(N\)-, \(O\)-, and glycolipid glycosylation with reduced sialic acid in glycans [137; 138; 97; 106; 128]. Glycosylation defects attributed to Golgi trafficking also characterized the phenotypes of COG mutants in \(S\). _cerevisiae_ at the restrictive temperature [139; 140; 141; 142]. In \(C\). _elegans_ COG1 and COG3 proteins are required for normal glycosylation and gonadal localization of MIG-17 protease, a member of the ADAM family proteins, which controls migration of gonadal distal tip cells [143]. Structural analysis of \(N\)-glycans by MS showed that _cog1_ mutant failed to form the fucose-rich \(N\)-glycans and to add fucose to residues on \(N\)-glycans. MS analysis also revealed an increase in high mannose and paucimmanose glycans in \(C\). _elegans_ cog1 mutants [129]. The _Drosophila_ homologues of human COG5, and COG7 are essential for male fertility, normal cytokinesis and spermatid differentiation [144; 145; 146]. Loss-of-function _Cog7_ mutations reduce life span and cause psychomotor defects in _Drosophila_ similar to _COG7-CDG_ patients [134]. Analysis of \(N\)-linked glycoprotein glycans by multidimensional ion trap mass spectrometry in heads of _Drosophila Cog7_ mutants, revealed altered N-linked glycome profiles with an increased abundance of high mannose and paucimmunose type glycans and of a family of neural-specific, dititcosylated \(N\)-glycans. Additionally, _Cog7_ mutants displayed hyposialylation. Thus, the phenotypic traits of the _Drosophila_ COG7-CDG disease model parallel the pathological characteristics of COG7-CDG patients, including neuromotor defects and defective \(N\)-glycome profiles. Additionally, _Drosophila Cog7_ mutants revealed defects in the larval neuromuscular junctions leading to a reduction in bouton numbers. Different defects in larval NMJs were observed in _Drosophila Cog1_ null mutants, which increased synaptic branch length without affecting bouton density [147]. Comparison of \(N\)-glycome alterations in _Cog1_ null mutants with those of _Cog7_ mutants should elucidate on the requirements for specific glycans in the larval NMJ architecture. The analysis of COG complex interactome in _Drosophila melanogaster_ confirmed the interaction with Rab1 and allowed to identify GOLPH3 as a novel molecular partner of Cog5 and Cog7 [134; 148]. Cog 7 protein is required for Golgi localization of GOLPH3 and facilitates GOLPH3 binding with the coatomer and Rab1 GTPase.