## 5 Gorab, a Scaffolding Protein for COPI, Is Involved in Geroderma Osteodysplastica
According to these data, GO can be considered as a type II congenital disorder of glycosylation (CDGs-II), affecting the tissues that are mostly dependent on protein glycosylation and glycanation, such as skin and bone. Indeed, these tissues present a large component of extracellular matrix; for this reason, they could be very sensitive to GORAB mutations [66; 87; 94]. The Vesicle Tethering COG Complex and Other Tethering Factors Are Required for Normal Glycosylation  
Recent work involved mutations in CCTs in glycosylation defects and CDGs. GMAP-210 functions as a tether for both ER-to-Golgi and intra-Golgi vesicles [95]. Loss-of-function mutations in the gene encoding GMAP-210 are associated with neonatal lethal skeletal dysplasia in mice and achondrogenesis type 1A in humans [96]. Mice carrying null mutations in _Trip11_, which encodes GMAP-210, displayed swollen ER and alterations of Golgi architecture in multiple tissues including cartilage [96]. Glycan processing defects in the Golgi were found in fibroblasts and chondrocytes of mice lacking GMAP-210, resulting in intracellular accumulation of perlecan, but not of type II collagen or aggrecan in chondrocytes. Similarly, fibroblasts from patients carrying either a heterozygous or homozygous nonsense mutant variant of GMAP-210 displayed incomplete glycosylation of the model secretory protein vesicular stomatitis virus G protein, indicating a link between altered glycan processing and GMAP-201 mediated vesicle tethering [96]. The requirement for the conserved oligomeric Golgi (COG) complex for normal Golgi-glycosylation has been demonstrated by a large amount of research data [20]. The eight-subunit COG complex, a member of the CATCHR family of tethers, regulates retrograde intra-Golgi vesicle trafficking [97; 98; 99; 100]. The COG complex consists of eight subunits and can exist as a hetero-octameric complex or two distinct subcomplexes: Lobe A (COG1-4) and Lobe B (COG5-8) [101; 102; 103]. COGI-COG8 interaction, through the formation of alpha-helical bundles, is required to bridge the two lobes together [101; 102; 104]. Lobe A predominantly associates with the Golgi membranes of every cisterna whereas Lobe B localizes to COPI vesicles [105]. Depletion of COG subunits in yeast and mammalian cells results in a massive accumulation of Golgi-derived vesicles of approximately 60 nm [106; 107; 108]. These vesicles called COG complex dependent (CCD) vesicles, are enriched in _medial/trans_-Golgi enzymes and intra-Golgi v-SNAREs and can be tethered in vitro by purified COG, demonstrating the role of COG as a tethering complex [109]. The COG complex has a central role in intra-Golgi trafficking due to its ability to associate with several vesicle trafficking players. Indeed, COG subunits were shown to interact with intra-Golgi SNAREs, SM proteins, COPI coat proteins, small Rab GTPases and CCTs [50; 110; 111]. Several studies indicate that the COG complex may coordinate tethering and vesicle fusion events [50]. Importantly the interaction of the COG complex subunit COG4 with SM proteins and SNAREs is required for the assembly of two different SNAREpin complexes, the intra-Golgi Stc5-GS28-Ykt6-GS15 and the _trans_-Golgi STX16/STX6/VT1A/VAMP4 [112; 113]. In humans, mutations in _COG1_, _COG2_, _COG4_-COG8_ cause inherited, autosomal recessive, congenital disorders of glycosylation CDGs-II, [114; 115; 116; 117; 118; 119; 120; 121; 122; 123; 124; 125]. Deficiencies in COG complex subunits (COG-CDG) have been linked to developmental impairments including microcephaly, mental retardation, hypothermia accompanied with dysmorphic features and feeding problems [114; 115; 116; 117; 118; 119; 120; 121; 122; 123; 124; 125]. Mutations in _COG7_ gene, cause the highest mortality within the first year of life [123; 124]. Glycan analysis by mass-spectrometry revealed hyposialylation of serum proteins, abnormal synthesis of \(N\)- and \(O\)-linked glycans and altered glycolipids in most COG-CDG patients [114; 119; 120; 122; 123; 124; 125].