Alternative titles; symbols
HGNC Approved Gene Symbol: COG5
SNOMEDCT: 721100009;
Cytogenetic location: 7q22.3 Genomic coordinates (GRCh38): 7:107,201,372-107,563,920 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q22.3 | Congenital disorder of glycosylation, type IIi | 613612 | Autosomal recessive | 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 COG5 (Ungar et al., 2002).
By database searching for sequences homologous to purified bovine COG5 protein, Walter et al. (1998) identified human ESTs containing partial COG5 sequences, which they called GOLTC1. They obtained the full-length cDNA by PCR amplification of the 5-prime end of the sequence with a HeLa cell library used as template and insertion of a missing exon predicted by the bovine sequence. Human GOLTC1 encodes a deduced 839-amino acid protein with a calculated molecular mass of 92.7 kD. It shares 81% sequence identity with the bovine protein. By sequence comparison of several putative GOLTC1 cDNAs with the genomic sequence, Walter et al. (1998) determined that GOLTC1 mRNA is alternatively spliced. By tissue fractionation, Western blot analysis, and immunohistochemistry, they identified both membrane and cytosolic pools of GOLTC1 and localized the membrane-associated pool to the Golgi apparatus. With the use of an in vitro intra-Golgi transport assay, Walter et al. (1998) purified and identified GOLTC1 as 1 of at least 5 proteins comprising a Golgi transport complex.
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, 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.
By sequence analysis, Walter et al. (1998) identified the COG5 gene within a BAC clone mapping to chromosome 7q31. Gross (2017) mapped the COG5 gene to chromosome 7q22.3 based on an alignment of the COG5 sequence (GenBank AF058718) with the genomic sequence (GRCh38).
In an Iraqi girl with congenital disorder of glycosylation (CDG2I; 613612), Paesold-Burda et al. (2009) identified a homozygous intronic substitution (606821.0001) leading to exon skipping and severely reduced expression of the COG5 protein. The mutation was associated with a mild psychomotor retardation with delayed motor and language development.
By direct sequencing of the COG5 gene in a 9-year-old Chinese girl with CDG2I, Fung et al. (2012) identified compound heterozygous mutations in the COG5 gene (606821.0002 and 606821.0003). Each parent was heterozygous for one of the mutations.
In 5 patients with CDG2I, including 2 Moroccan sibs, an Italian and a Belgian patient, and the patient reported by Fung et al. (2012), Rymen et al. (2012) identified homozygous or compound heterozygous mutations in the COG5 gene (606821.0002-606821.0007). The mutations were found by whole-exome and/or Sanger sequencing.
In an 11-year-old Chinese boy with CDG2I, Yin et al. (2019) identified compound heterozygous mutations in the COG5 gene (606821.0008 and 606821.0009) by whole-exome sequencing. Each parent was heterozygous for one of the mutations.
In a 4-year-old Chinese girl with CDG2I, Wang et al. (2020) identified compound heterozygous mutations in the COG5 gene (606821.0010 and 606821.0011) by whole-exome sequencing. The mutations segregated with the disorder in the family.
In a 12-year-old Iraqi girl, born of consanguineous parents, with a congenital disorder of glycosylation (CDG2I; 613612), Paesold-Burda et al. (2009) identified a homozygous T-to-C transition in intron 14 of the COG5 gene (1669-15T-C), resulting in altered splicing and a transcript lacking the 58 amino acids of exons 15 and 16. The mutation was not detected in 150 control alleles or 50 alleles from the same geographic region as the patient's family. Low levels of full-length COG5 were detected in patient fibroblasts, but the truncated protein could not be detected, suggesting it was unstable and prone to degradation. The girl exhibited mild hypotonia, mild ataxia, and moderate mental retardation. Brain MRI revealed atrophy of the cerebellum and brainstem. Biochemical analyses of serum transferrin, haptoglobin, and alpha-1-acid glycoprotein revealed defects in both N- and O-glycosylation. Retrograde Golgi-to-endoplasmic reticulum trafficking was markedly delayed in the patient fibroblasts upon brefeldin-A treatment, which is a hallmark of COG deficiency. The trafficking delay could be restored to normal values by expressing a wildtype COG5 cDNA in the patient cells. Paesold-Burda et al. (2009) suggested that CDG should be considered when investigating the basis of even mild neurologic impairments in children.
In a 9-year-old Chinese girl with congenital disorder of glycosylation IIi (CDG2I; 613612), Fung et al. (2012) and Rymen et al. (2012)identified compound heterozygous mutations in the COG5 gene: a deletion of AGTAA and an insertion of CT at nucleotide 556 (c.556_560delAGTAAinsCT), resulting in a Ser186_Lys187delinsLeu protein change, and a c.95T-G transversion, resulting in a met32-to-arg (M32R; 606821.0003) substitution. (Fung et al. (2012) had cited the second mutation as a c.1856T-C transversion, resulting in an ile619-to-thr (I619T) substitution). The mutations segregated with the disorder in the family Fung et al. (2012) reported that serum transferrin isoelectric focusing showed a type 2 pattern and serum apolipoprotein C-III showed a decrease in the disialo isoform and an increase in the asialo isoform. Analysis of serum transferrin glycans showed evidence of hyposialylation. Rymen et al. (2012) studied fibroblasts from this patient and found a delay in redistribution of GalT-GFP into the endoplasmic reticulum compared to control, suggesting a defect in retrograde trafficking. Patient fibroblasts also showed a significant decrease in steady-state levels of the COG5 protein compared to control.
For discussion of the c.95T-G transversion in the COG5 gene, resulting in a met32-to-arg (M32R) substitution, that was found in compound heterozygous state in a Chinese girl with congenital disorder of glycosylation type IIi (CDGIi; 613612) by Rymen et al. (2012), see 606821.0002.
In 2 Moroccan sibs with congenital disorder of glycosylation IIi (CDG2I; 613612), born to consanguineous parents, Rymen et al. (2012) identified a homozygous c.2518G-T transversion in the COG5 gene, resulting in a glu840-to-ter (E840X) substitution. The mutations were identified by whole-exome sequencing in first sib and confirmed by Sanger sequencing in the second sib. A third sib had clinical features of CDG2I but did not have genetic confirmation. The sibs showed a type 2 pattern on transferrin isoelectric focusing, and analysis of N-glycans of serum transferrin suggested a defect in sialylation and a mild defect in galactosylation. Studies in fibroblasts from one of the sibs showed a significant decrease in steady-state levels of the COG5 protein as well as a delay in redistribution of GalT-GFP into the endoplasmic reticulum compared to controls, suggesting a defect in retrograde trafficking.
In a 3-year-old Italian boy with congenital disorder of glycosylation IIi (CDG2I; 613612) Rymen et al. (2012) identified compound heterozygous mutations in the COG5 gene: a 1-bp deletion (c.189delG), resulting in a frameshift and premature termination (Cys64ValfsTer6), and a 3-bp insertion (c.2338_2340dupATT; 606821.0006), resulting in duplication of isoleucine at amino acid position 780 (I780dup). The mutations were identified by Sanger sequencing. The I780dup mutation was not present in the dbSNP or 1000 Genomes Project databases. The patient showed a type 2 pattern on transferrin isoelectric focusing, and analysis of N-glycans of serum transferrin in serum suggested a defect in sialylation and a mild defect in galactosylation. Studies in fibroblasts from this patient showed a significant decrease in steady-state levels of the COG5 protein as well as a delay in redistribution of GalT-GFP into the endoplasmic reticulum compared to controls, suggesting a defect in retrograde trafficking.
For discussion of the 3-bp insertion (c.2338_2340dupATT) in the COG5 gene, resulting in duplication of isoleucine at amino acid position 780 (I780dup), that was found in a patient with congenital disorder of glycosylation IIi (CDG2I; 613612) by Rymen et al. (2012), see 606821.0005.
In a 3-year-old Belgian boy with congenital disorder of glycosylation IIi (CDG2I; 613612), Rymen et al. (2012) identified a homozygous c.1780G-T transversion in the COG5 gene, resulting in a val594-to-phe (V594F) substitution The mutation was identified by Sanger sequencing. The patient had a type 2 pattern on transferrin isoelectric focusing, and analysis of N-glycans of serum transferrin in serum suggested a defect in sialylation. Studies in fibroblasts from this patient showed a significant decrease in steady-state levels of the COG5 protein as well as a delay in redistribution of GalT-GFP into the endoplasmic reticulum compared to controls, suggesting a defect in retrograde trafficking.
In an 11-year-old Chinese boy with congenital disorder of glycosylation IIi (CDG2I; 613612), Yin et al. (2019) identified compound heterozygous mutations in the COG5 gene: a 1-bp deletion (c.330delT, NM_006348.3), predicting a frameshift and a premature termination codon (Val111LeufsTer22), and a c.2324C-T transition, resulting in a pro775-to-leu (P775L; 606821.0009) substitution. Each parent was heterozygous for one of the mutations. Neither mutation was present in the 1000 Genomes Project, ExAC, or gnomAD databases. Functional studies were not performed.
For discussion of the c.2324C-T transition (c.2324C-T, NM_006348.3) in the COG5 gene, resulting in a pro775-to-leu (P775L) substitution, that was found in compound heterozygous state in a patient with congenital disorder of glycosylation IIi (CDG2I; 613612) by Yin et al. (2019), see 606821.0008.
In a 4-year-old Chinese girl with congenital disorder of glycosylation IIi (CDG2I; 613612), Wang et al. (2020) identified compound heterozygous mutations in the COG5 gene: a c.1290C-A transversion (c.1290C-A, NM_006348), resulting in a tyr430-to-ter (Y430X) substitution, and a c.2077A-C transversion, resulting in a thr693-to-pro (T693P; 606821.0011) substitution at a highly conserved residue. The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. Each parent was heterozygous for one of the mutations. Western blot analysis in patient leukocytes revealed decreased expression of the full-length COG5 protein and the presence of a smaller protein product compared to wildtype. The Y430X mutation had a low frequency in the ExAC, 1000 Genomes Project, and gnomAD databases. The T693P mutation was absent from the 1000 Genomes database and had a low frequency in the ExAC and gnomAD databases. Functional studies were not performed.
For discussion of the c.2077A-C transversion (c.2077A-C, NM_006348) in the COG5 gene, resulting in a thr693-to-pro (T693P) substitution, that was found in compound heterozygous state in a patient with congenital disorder of glycosylation IIi (CDG2I; 613612) by Wang et al. (2020), see 606821.0010.
Fung, C. W., Matthijs, G., Sturiale, L., Garozzo, D., Wong, K. Y., Wong, R., Wong, V., Jaeken, J. COG5-CDG with a mild neurohepatic presentation. JIMD Rep. 3: 67-70, 2012. [PubMed: 23430875] [Full Text: https://doi.org/10.1007/8904_2011_61]
Gross, M. B. Personal Communication. Baltimore, Md. 3/27/2017.
Paesold-Burda, P., Maag, C., Troxler, H., Foulquier, F., Kleinert, P., Schnabel, S., Baumgartner, M., Hennet, T. Deficiency in COG5 causes a moderate form of congenital disorders of glycosylation. Hum. Molec. Genet. 18: 4350-4356, 2009. [PubMed: 19690088] [Full Text: https://doi.org/10.1093/hmg/ddp389]
Rymen, D., Keldermans, L., Race, V., Regal, L., Deconinck, N., Dionisi-Vici, C., Fung, C., Sturiale, L., Rosnoblet, C., Foulquier, F., Matthijs, G., Jaeken, J. COG5-CDG: expanding the clinical spectrum. Orphanet J. Rare Dis. 7: 94, 2012. Note: Electronic Article. Note: Erratum: Orphanet J. Rare Dis. 8: 120 only, 2013. [PubMed: 23228021] [Full Text: https://doi.org/10.1186/1750-1172-7-94]
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]
Walter, D. M., Paul, K. S., Waters, M. G. Purification and characterization of a novel 13 S hetero oligomeric protein complex that stimulates in vitro Golgi transport. J. Biol. Chem. 273: 29565-29576, 1998. [PubMed: 9792665] [Full Text: https://doi.org/10.1074/jbc.273.45.29565]
Wang, X., Han, L., Wang, X.-Y., Wang, J.-H., Li, X.-M., Jin, C.-H., Wang, L. Identification of two novel mutations in COG5 causing congenital disorder of glycosylation. Front. Genet. 11: 168, 2020. Note: Electronic Article. [PubMed: 32174980] [Full Text: https://doi.org/10.3389/fgene.2020.00168]
Yin, S., Gong, L., Qiu, H., Zhao, Y., Zhang, Y., Liu, C., Jiang, H., Mao, Y., Kong, L.-Y., Liang, B., Lv, Y. Novel compound heterozygous COG5 mutations in a Chinese male patient with severe clinical symptoms and type IIi congenital disorder of glycosylation: a case report. Exp. Ther. Med. 18: 2695-2700, 2019. [PubMed: 31572517] [Full Text: https://doi.org/10.3892/etm.2019.7834]