HGNC Approved Gene Symbol: COG7
SNOMEDCT: 717773005;
Cytogenetic location: 16p12.2 Genomic coordinates (GRCh38) : 16:23,388,493-23,453,189 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p12.2 | Congenital disorder of glycosylation, type IIe | 608779 | 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 COG7 (Ungar et al., 2002).
By SDS-PAGE analysis of bovine brain cytosol, Ungar et al. (2002) identified the 8 subunits of the COG complex. Mass spectrometric and database analysis led to the identification of a cDNA encoding COG7. The deduced 770-amino acid COG7 protein is conserved in plants and invertebrates, but not in yeast or worms. Immunofluorescence microscopy demonstrated that COG1 (LDLB; 606973) colocalizes with COG7, 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.
By genomic sequence analysis, Ungar et al. (2002) determined that the COG7 gene contains 17 exons.
By genomic sequence analysis, Ungar et al. (2002) mapped the COG7 gene to chromosome 16p.
Wu et al. (2004) described 2 sibs with a congenital disorder of glycosylation, which they designated type IIe (CDG2E; 608779), caused by homozygous mutation in the COG7 gene (606978.0001). The patients were found to have disruption of multiple glycosylation pathways similar to that seen in Chinese hamster ovary cell lines with mutations in genes encoding COG1 (606973) and COG2 (606974). COG7 was undetectable in the fibroblasts of both patients, and sequencing revealed that both had a homozygous intronic mutation (IVS1+4A-C; 606978.0001). The mutation impairs the integrity of the COG complex and alters Golgi trafficking, thus disrupting the glycosylation process.
Morava et al. (2007) reported 3 patients from 2 unrelated consanguineous Moroccan families with a fatal form of CDG in whom they identified homozygosity for the IVS1+4A-C mutation reported by Wu et al. (2004).
Ng et al. (2007) identified homozygosity for the recurrent IVS1+4A-C mutation in the COG7 gene in a Moroccan girl, born of consanguineous parents, with CDG2E.
In 2 sibs with congenital disorder of glycosylation type IIe (CDG2E; 608779), Wu et al. (2004) identified a homozygous A-to-C transversion at position +4 in the first intron of the COG7 gene (IVS1+4A-C), which allows use of an alternative splice site near the first exon/intron boundary and results in a 19-bp deletion. The patients had perinatal asphyxia and dysmorphia, including low-set dysplastic ears, micrognathia, short neck, and loose, wrinkled skin. Generalized hypotonia, hepatosplenomegaly, and progressive jaundice developed shortly after birth. On x-ray, the male sib lacked humeral and tibial epiphyses, whereas the female had short extremities. The male also had a large space at the cisterna cerebelli superior on CT scan. Both sibs developed severe epilepsy and died from recurrent infections and cardiac insufficiency, the male at 5 weeks of age and the female at 10 weeks. The parents were consanguineous, and an earlier-born sib had died shortly after birth with similar congenital defects.
In 2 sibs and another child from 2 unrelated consanguineous Moroccan families with a fatal form of CDG, Morava et al. (2007) identified homozygosity for the IVS1+4A-C mutation in the COG7 gene, which disrupts the splice donor site and activates at least 2 different cryptic splice sites, leading to a 19-bp deletion and an 83-bp deletion. The phenotype was similar to that of the 2 sibs previously described by Wu et al. (2004), except for lack of skeletal anomalies and only mild liver involvement in these patients. The parents and a healthy sib from 1 of the families were heterozygous for the mutation.
Ng et al. (2007) identified homozygosity for the intron 1 transversion in a Moroccan girl with CDG IIe who was born of consanguineous parents. She had a flat face, full lips, protruding tongue, and inverted nipples. Other features included hepatomegaly with abnormal liver enzymes, severe hypotonia, and distal arthrogryposis. She later developed seizures, had poor ocular fixation, little development, and polyneuropathy. Brain MRI showed delayed myelination. She died at age 3.5 months of respiratory insufficiency associated with laryngeal spasm.
In 2 brothers, born of consanguineous Moroccan parents, with congenital disorder of glycosylation type IIe (CDG2E; 608779), Zeevaert et al. (2009) identified a homozygous IVS1-7A-G transition in intron 1 of the COG7 gene, resulting in a new splice acceptor site and insertion of an alanine and threonine at codons 57 and 57. Western blot analysis showed 68% residual COG7 protein levels. A younger sib was also affected. Both sibs appeared normal at birth and had no dysmorphic features, but symptoms appeared at 1 month and 10 months, respectively. The proband developed diarrhea with severe dehydration, hepatomegaly, cholestasis, anemia, thrombocytopenia, and mild proteinuria. Brain MRI showed cerebral atrophy and a hypodensity in the periventricular white matter. Psychomotor development was delayed and there was hypotonia, areflexia of the lower limbs, and failure to thrive. He died of high fever of unknown origin at age 17 months. The younger sib showed psychomotor retardation, feeling problems, behavioral problems, and elevated serum transaminases at age 10 months. He had poor growth, but was alive at age 4.5 years. DNA from the younger sib was not available. Biochemical studies of patient fibroblasts showed a defect in retrograde vesicular transport of the Golgi.
Morava, E., Zeevaert, R., Korsch, E., Huijben, K., Wopereis, S., Matthijs, G., Keymolen, K., Lefeber, D. J., De Meirleir, L., Wevers, R. A. A common mutation in the COG7 gene with a consistent phenotype including microcephaly, adducted thumbs, growth retardation, VSD and episodes of hyperthermia. Europ. J. Hum. Genet. 15: 638-645, 2007. Note: Erratum: Europ. J. Hum. Genet. 15: 819 only, 2007. [PubMed: 17356545] [Full Text: https://doi.org/10.1038/sj.ejhg.5201813]
Ng, B. G, Kranz, C., Hagebeuk, E. E. O., Duran, M., Abeling, N. G. G. M., Wuyts, B., Ungar, D., Lupashin, V., Hartdorff, C. M., Poll-The, B. T., Freeze, H. H. Molecular and clinical characterization of a Moroccan Cog7 deficient patient. Molec. Genet. Metab. 91: 201-204, 2007. [PubMed: 17395513] [Full Text: https://doi.org/10.1016/j.ymgme.2007.02.011]
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]
Wu, X., Steet, R. A., Bohorov, O., Bakker, J., Newell, J., Krieger, M., Spaapen, L., Kornfeld, S., Freeze, H. H. Mutation of the COG complex subunit gene COG7 causes a lethal congenital disorder. Nature Med. 10: 518-523, 2004. [PubMed: 15107842] [Full Text: https://doi.org/10.1038/nm1041]
Zeevaert, R., Foulquier, F., Cheillan, D., Cloix, I., Guffon, N., Sturiale, L., Garozzo, D., Matthijs, G., Jaeken, J. A new mutation in COG7 extends the spectrum of COG subunit deficiencies. Europ. J. Med. Genet. 52: 303-305, 2009. [PubMed: 19577670] [Full Text: https://doi.org/10.1016/j.ejmg.2009.06.006]