Alternative titles; symbols
HGNC Approved Gene Symbol: COG4
SNOMEDCT: 718751000;
Cytogenetic location: 16q22.1 Genomic coordinates (GRCh38): 16:70,480,567-70,523,554 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16q22.1 | Congenital disorder of glycosylation, type IIj | 613489 | Autosomal recessive | 3 |
| Saul-Wilson syndrome | 618150 | Autosomal dominant | 3 |
Multiprotein complexes are key determinants of Golgi apparatus structure and its capacity for intracellular transport and glycoprotein modification. Several complexes have been identified, including the Golgi transport complex (GTC), the LDLC complex, which is involved in glycosylation reactions, and the SEC34 complex, which is involved in vesicular transport. These 3 complexes are identical and have been termed the conserved oligomeric Golgi (COG) complex, which includes COG4 (Ungar et al., 2002).
By database searching for sequences homologous to the yeast complexed with Dor1 (COG8; 606979) (COD) proteins, Whyte and Munro (2001) identified cDNAs encoding COG4, which they called COD1, and other members of the COG complex. The deduced 785-amino acid COG4 protein contains an N-terminal coiled-coil region. Coiled-coil regions are found in all members of the COG complex and may be involved in holding the complex together or in binding other proteins involved in vesicle docking and fusion.
By SDS-PAGE analysis of bovine brain cytosol, Ungar et al. (2002) identified the 8 subunits of the COG complex. Immunofluorescence microscopy demonstrated that COG1 (LDLB; 606973) colocalizes with COG7 (606978), as well as with COG3 (606975) and COG5 (606821), with a Golgi marker in a perinuclear distribution. Immunoprecipitation analysis showed that all COG subunits interact with COG2 (LDLC; 606974). Ungar et al. (2002) concluded that the COG complex is critical for the structure and function of the Golgi apparatus and can influence intracellular membrane trafficking.
Richardson et al. (2009) determined the crystal structure of the C-terminal 250 residues of human COG4. The Arg729 residue (see 606976.0001) resides at the center of a salt bridge network that stabilizes a small C-terminal domain.
Reynders et al. (2009) noted that the COG4 gene maps to chromosome 16q22.1.
Using coimmunoprecipitation analysis and pull-down assays in human cells, Laufman et al. (2009) found that SLY1 (SCFD1; 618207) interacted with the COG complex via the COG4 subunit. Mutation analysis revealed that amino acids 1 to 84 of COG4 contained a SLY1-binding site, with residues glu53 and glu71 playing a crucial role in SLY1 binding. The authors noted that this region of COG4 is highly conserved throughout evolution, with the exception of the S. cerevisiae ortholog. Further analysis showed that the COG4-SLY1 interaction was required for colocalization of SNARE complex proteins and for assembly of the complex. Disruption of the COG4-SLY1 interaction impaired pairing of SNAREs involved in intra-Golgi transport and thereby attenuated Golgi-to-ER retrograde transport.
Congenital Disorder of Glycosylation, Type IIj
Reynders et al. (2009) reported a Portuguese patient with congenital disorder of glycosylation type IIj (CDG2J; 613489) and identified compound heterozygosity for a missense mutation in the COG4 gene (606976.0001) and a large deletion encompassing most of the COG4 gene and part of the FUK gene (608675) (606976.0002).
In an Indian child with a severe form of CDG2J, originally reported by Miura et al. (2005), Ng et al. (2011) identified compound heterozygosity for 2 mutations in the COG4 gene (606976.0003-606976.0004).
Saul-Wilson Syndrome
In 14 patients with Saul-Wilson syndrome (SWILS; 618150), including patient 2 in the report of Saul and Wilson (1990) and patient 1 in the report of Hersh et al. (1994), Ferreira et al. (2018) identified 2 different de novo heterozygous mutations in the COG4 gene, c.1546G-A (606976.0005) and c.1546G-C (606976.0006), both of which give rise to an identical missense mutation (G516R). The mutations, which were found by whole-exome or whole-genome sequencing, were confirmed by Sanger sequencing. Ferreira et al. (2018) found that the subcellular localization of COG subunits was not altered in the patients. Patient fibroblasts exhibited delayed anterograde vesicular trafficking from the endoplamic reticulum (ER) to the Golgi and accelerated retrograde vesicular recycling from the Golgi to the ER. This altered steady-state equilibrium led to a decrease in Golgi volume, as well as morphologic abnormalities with collapse of the Golgi stacks. Despite these abnormalities of the Golgi apparatus, protein glycosylation in patient sera and fibroblasts was not notably altered, but decorin (125255), a proteoglycan secreted into the extracellular matrix, showed altered Golgi-dependent glycosylation.
Reynders et al. (2009) reported a Portuguese boy with congenital disorder of glycosylation type IIj (CDG2J; 613489) and identified compound heterozygosity for a 2185C-T transition in exon 18 of the COG4 gene, resulting in an arg729-to-trp (R729W) substitution at a conserved residue, and a large deletion (606976.0002) of approximately 400 kb with the distal breakpoint between intron 2 and exon 5 of the COG4 gene and the proximal breakpoint upstream of the FUK gene (608675). The FUK gene encodes L-fucose kinase, which is necessary for the reutilization of fucose after the degradation of oligosaccharides. Because no decreased fucosylation was observed in the N-glycans of the patient, the authors concluded that the 'partial monosomy' of this gene was not pathogenic. The R729W mutation was not identified in over 100 European control alleles. Western blot analysis of patient fibroblasts showed reduced COG4 protein levels compared to control, and downregulation of COG4 expression additionally affected expression or stability of other lobe A subunits. Despite this, full complex formation was maintained albeit to a lower extent. Subunits were present in a cytosolic pool and full complex formation assisted tethering preceding membrane fusion. The unrelated father and mother were heterozygous for the R729W mutation or the deletion, respectively, and Western blot analysis of parental fibroblasts showed normal COG4 protein levels.
By determining the crystal structure of a COG4 C-terminal fragment, Richardson et al. (2009) determined that the R729 residue occupies a key position at the center of a salt bridge network, thereby stabilizing the small C-terminal domain. Knockdown of COG4 in HeLa cells by use of a COG4-specific shRNA plasmid resulted in disruption of glycosylation of cell surface proteins. A full-length COG4 containing the R729W mutation failed to rescue the glycosylation defect in these knockdown cells.
For discussion of the large deletion with the distal breakpoint between intron 2 and exon 5 of the COG4 gene and the proximal breakpoint upstream of the FUK gene (608675) that was found in compound heterozygous state in a patient with congenital disorder of glycosylation type IIj (CDG2J; 613489) by Reynders et al. (2009), see 606976.0001.
In an Indian child with congenital disorder of glycosylation type IIj (CDG2J; 613489), Ng et al. (2011) identified compound heterozygosity for 2 mutations in the COG4 gene: a 697G-T transversion in exon 5 resulting in a glu233-to-ter (E233X) substitution, and a 2318T-G transversion in exon 19 resulting in a leu773-to-arg (L773R; 606976.0004) substitution. The L773R mutation was inherited from the unaffected mother, but the E233X mutation was not found in either parent, consistent with a de novo occurrence. Most of the E233X unstable transcript was subject to nonsense-mediated mRNA decay. The patient had profound developmental delay, hypotonia, failure to thrive, seizures, coagulopathy, liver cirrhosis, and recurrent infections that were ultimately fatal around age 2 years. The patient had 2 unaffected sibs. Patient serum N-glycans showed deficiencies in both sialylation and galactosylation, and patient fibroblasts showed impaired O-glycosylation, indicating a combined deficiency. Patient fibroblasts also showed a defect in Brefeldin A (BFA)-induced retrograde transport of Golgi proteins back to the endoplasmic reticulum. There was an isolated reduction in COG4 protein expression.
For discussion of the leu773-to-arg (L773R) mutation in the COG4 gene that was found in compound heterozygous state in a patient with congenital disorder of glycosylation type IIj (CDG2J; 613489) by Ng et al. (2011), see 606976.0003.
In 11 patients with Saul-Wilson syndrome (SWILS; 618150), including patient 1 in the report of Hersh et al. (1994), Ferreira et al. (2018) identified a de novo heterozygous c.1546G-A transition (c.1546G-A, NM_015386.2) in the COG4 gene, resulting in a gly516-to-arg (G516R) substitution. The mutations, which were found by whole-exome or whole-genome sequencing, were confirmed by Sanger sequencing. Compared to control cell lines, fibroblasts from affected individuals showed normal mRNA expression and protein level of COG4 and other COG subunits, confirming that the variant leads to production of a stable protein. Protein modeling predicted the loss of a loop structure in the mutant protein; however, binding of COG4 to other COG subunits was not altered.
In 3 patients with Saul-Wilson syndrome (SWILS; 618150), including patient 2 in the report of Saul and Wilson (1990), Ferreira et al. (2018) identified a de novo heterozygous c.1546G-C transversion (c.1546G-C, NM_015386.2) in the COG4 gene, resulting in a gly516-to-arg (G516R) substitution. The mutations, which were found by whole-exome or whole-genome sequencing, were confirmed by Sanger sequencing. Compared to control cell lines, fibroblasts from affected individuals showed normal mRNA expression and protein level of COG4 and other COG subunits, confirming that the variant leads to production of a stable protein. Protein modeling predicted the loss of a loop structure in the mutant protein; however, binding of COG4 to other COG subunits was not altered.
Ferreira, C. R., Xia, Z.-J., Clement, A., Parry, D. A., Davids, M., Taylan, F., Sharma, P., Turgeon, C. T., Blanco-Sanchez, B., Ng, B. G., Logan, C. V., Wolfe, L. A., and 44 others. A recurrent de novo heterozygous COG4 substitution leads to Saul-Wilson syndrome, disrupted vesicular trafficking, and altered proteoglycan glycosylation. Am. J. Hum. Genet. 103: 553-567, 2018. [PubMed: 30290151] [Full Text: https://doi.org/10.1016/j.ajhg.2018.09.003]
Hersh, J. H., Joyce, M. R., Spranger, J., Goatley, E. C., Lachman, R. S., Bhatt, S., Rimoin, D. L. Microcephalic osteodysplastic dysplasia. Am. J. Med. Genet. 51: 194-199, 1994. [PubMed: 8074143] [Full Text: https://doi.org/10.1002/ajmg.1320510304]
Laufman, O., Kedan, A., Hong, W., Lev, S. Direct interaction between the COG complex and the SM protein, Sly1, is required for Golgi SNARE pairing. EMBO J. 28: 2006-20017, 2009. [PubMed: 19536132] [Full Text: https://doi.org/10.1038/emboj.2009.168]
Miura, Y., Tay, S. K. H., Aw, M. M., Eklund, E. A., Freeze, H. H. Clinical and biochemical characterization of a patient with congenital disorder of glycosylation (CDG) IIX. J. Pediat. 147: 851-853, 2005. [PubMed: 16356446] [Full Text: https://doi.org/10.1016/j.jpeds.2005.07.038]
Ng, B. G., Sharma, V., Sun, L., Loh, E., Hong, W., Tay, S. K. H., Freeze, H. H. Identification of the first COG-CDG patient of Indian origin. Molec. Genet. Metab. 102: 364-367, 2011. [PubMed: 21185756] [Full Text: https://doi.org/10.1016/j.ymgme.2010.11.161]
Reynders, E., Foulquier, F., Teles, E. L., Quelhas, D., Morelle, W., Rabouille, C., Annaert, W., Matthijs, G. Golgi function and dysfunction in the first COG4-deficient CDG type II patient. Hum. Molec. Genet. 18: 3244-3256, 2009. [PubMed: 19494034] [Full Text: https://doi.org/10.1093/hmg/ddp262]
Richardson, B. C., Smith, R. D., Ungar, D., Nakamura, A., Jeffrey, P. D., Lupashin, V. V., Hughson, F. M. Structural basis for a human glycosylation disorder caused by mutation of the COG4 gene. Proc. Nat. Acad. Sci. 106: 13329-13334, 2009. [PubMed: 19651599] [Full Text: https://doi.org/10.1073/pnas.0901966106]
Saul, R. A., Wilson, W. G. A 'new' skeletal dysplasia in two unrelated boys. Am. J. Med. Genet. 35: 388-393, 1990. [PubMed: 2309787] [Full Text: https://doi.org/10.1002/ajmg.1320350315]
Ungar, D., Oka, T., Brittle, E. E., Vasile, E., Lupashin, V. V., Chatterton, J. E., Heuser, J. E., Krieger, M., Waters, M. G. Characterization of a mammalian Golgi-localized protein complex, COG, that is required for normal Golgi morphology and function. J. Cell Biol. 157: 405-415, 2002. [PubMed: 11980916] [Full Text: https://doi.org/10.1083/jcb.200202016]
Whyte, J. R. C., Munro, S. The Sec34/35 Golgi transport complex is related to the exocyst, defining a family of complexes involved in multiple steps of membrane traffic. Dev. Cell 1: 527-537, 2001. [PubMed: 11703943] [Full Text: https://doi.org/10.1016/s1534-5807(01)00063-6]