Alternative titles; symbols
HGNC Approved Gene Symbol: COG6
SNOMEDCT: 1220574003, 773553003;
Cytogenetic location: 13q14.11 Genomic coordinates (GRCh38) : 13:39,655,627-39,791,666 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 13q14.11 | Congenital disorder of glycosylation, type IIl | 614576 | Autosomal recessive | 3 |
| Shaheen syndrome | 615328 | 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 COG6 (Ungar et al., 2002).
By screening for cDNAs with the potential to encode large proteins expressed in brain, Hirosawa et al. (1999) identified a partial cDNA encoding COG6, which they called KIAA1134. RT-PCR analysis detected weak expression in brain and ovary, with little or no expression in other tissues tested. Within brain, expression was highest in amygdala and cerebellum.
By database searching for sequences homologous to the yeast complexed with Dor1 (COG8; 606979) (COD) proteins, Whyte and Munro (2001) identified cDNAs encoding COG6, which they called COD2, and other members of the COG complex. The deduced 653-amino acid COG6 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.
By radiation hybrid analysis, Hirosawa et al. (1999) mapped the COG6 gene to chromosome 13.
Congenital Disorder of Glycosylation Type IIl
In a patient with fatal congenital disorder of glycosylation type IIl (CDG2L; 614576), Lubbehusen et al. (2010) identified a homozygous mutation in the COG6 gene (G549V; 606977.0001). The patient had intractable seizures, vomiting, loss of consciousness, intracranial bleeding due to vitamin K deficiency, and death at age 5 weeks. Biochemical studies of serum transferrin showed loss of galactose and sialic acid residues, and additional studies showed a combined defect in N- and O-glycosylation. Northern blot analysis showed reduced COG6 mRNA (15% of controls), indicating instability of the mutant transcript. The pathogenicity of the variant identified by Lubbehusen et al. (2010) was called into question by Shaheen et al. (2013).
Huybrechts et al. (2012) found homozygosity for the G549V mutation in the COG6 gene in a 27-month-old girl, born of consanguineous Moroccan parents, with CDG2L. She had severe failure to thrive, combined immunodeficiency with recurrent infections, hepatomegaly with cirrhosis, mild neurodevelopmental delay, microcephaly, and inflammatory bowel disease. Huybrechts et al. (2012) noted the phenotypic differences from the patient reported by Lubbehusen et al. (2010), and suggested that other factors must modify the disease course.
In 6 patients, including 2 sibs, with CDG2L, Rymen et al. (2015) identified a homozygous or compound heterozygous mutations in the COG6 gene (see, e.g., 606977.0001; 606977.0003-606977.0006). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing and/or by targeted sequencing of CDG gene panels. Functional studies of the variants and studies of patient cells were not performed, but the variants were predicted to result in a loss of function.
Shaheen Syndrome
In 12 patients from 3 consanguineous Saudi families with Shaheen syndrome (SHNS; 615328), Shaheen et al. (2013) identified a homozygous splice site mutation in the COG6 gene (606977.0001), resulting in decreased levels of the COG6 and STX6 (603944) proteins. The mutation, which was identified by homozygosity mapping and exome sequencing, segregated with the disorder. The patients had mental retardation, hypohidrosis resulting in episodic hyperthermia, enamel hypoplasia with dental caries, and hyperkeratosis of the palms and soles. Immunohistochemical analysis showed that COG6 is expressed in sweat glands, but skin biopsy from a patient showed normal structure and density, suggesting a functional defect. Isoelectric focusing of serum transferrin was repeatedly normal, showing no glycosylation defects. Shaheen et al. (2013) noted the phenotypic differences from the patient reported by Lubbehusen et al. (2010) and called into question the pathogenicity of the variant identified in that patient (606977.0001).
In a patient, born of unrelated Turkish parents, with fatal congenital disorder of glycosylation type IIl (CDG2L; 614576), Lubbehusen et al. (2010) identified a homozygous 1646G-T transversion in the COG6 gene, resulting in a gly549-to-val (G549V) substitution in a highly conserved residue. The mutation was not found in 100 control alleles. Northern blot analysis showed reduced COG6 mRNA (15% of controls), indicating instability of the mutant transcript. Retroviral gene transfer of wildtype COG6 corrected COG complex defects in patient fibroblasts.
Huybrechts et al. (2012) found homozygosity for the G549V mutation in a 27-month-old girl, born of consanguineous Moroccan parents, with CDG2L. She had severe failure to thrive, combined immunodeficiency with recurrent infections, hepatomegaly with cirrhosis, mild neurodevelopmental delay, microcephaly, and inflammatory bowel disease. Huybrechts et al. (2012) noted the phenotypic differences from the patient reported by Lubbehusen et al. (2010), and suggested that other factors must modify the disease course.
Shaheen et al. (2013) suggested that the G549V substitution identified by Lubbehusen et al. (2010) may not be pathogenic. The G549 residue is not strongly conserved among humans, and overexpression of the mutant protein was not studied in transfection rescue experiments.
Haijes et al. (2014) maintained that the G549V variant is pathogenic, noting that it was also reported by Huybrechts et al. (2012) and that Lubbehusen et al. (2010) had demonstrated in vitro that decreased amounts of the COG6 protein were caused by instability of the mutant transcript. In a response, Alkuraya and Shaheen (2014) stated that conclusive evidence that the G549V variant is pathogenic remains lacking.
In 2 brothers (P4.1 and P4.2) with CDG2L, who were said to be cousins of the patient reported by Lubbehusen et al. (2010) and to be born of unrelated Moroccan parents, Rymen et al. (2015) identified the G549V mutation in compound heterozygous state with another missense mutation (Y262C; 606977.0005) in the COG6 gene. (In the article by Rymen et al. (2015), this mutation is correctly stated as G549V in the text, but incorrectly stated as G594V in Table 1.)
In 12 patients from 3 consanguineous Saudi families with Shaheen syndrome (SHNS; 615328), Shaheen et al. (2013) identified a homozygous A-to-G transition in intron 12 of the COG6 gene (c.1167-24A-G), resulting in a splice site alteration. RT-PCR analysis showed a reduced level of the normal transcript, and high levels of an aberrant transcript causing a frameshift and premature termination (Gly390PhefsTer6). Western blot analysis of patient cells showed a 70% reduction in COG6 protein levels and decreased levels of STX6 (603944), an interacting protein. The mutation, which was identified by homozygosity mapping and exome sequencing, segregated with the disorder. Isoelectric focusing of serum transferrin was repeatedly normal, showing no glycosylation defects.
In an infant (P1), born of unrelated Bulgarian parents, with congenital disorder of glycosylation type IIl (CDG2L; 614576) resulting in death at 1 month of age, Rymen et al. (2015) identified a homozygous c.511C-T transition (c.511C-T, NM_001145079) in exon 5 of the COG6 gene, resulting in an arg171-to-ter (R171X) substitution. The mutation, which was found by whole-exome sequencing and filtered by a panel of CDG genes, was confirmed by Sanger sequencing and segregated with the disorder in the family. An unrelated 12-year-old girl (P6.1) of Turkish descent was compound heterozygous for R171X and an intronic T-to-G transversion (c.1746+2T-G; 606977.0004), resulting in a splice defect. These mutations were identified by Sanger sequencing of the COG6 gene based on a candidate gene approach. Functional studies of the variants and studies of patient cells were not performed, but the variants were predicted to result in a loss of function.
In a male infant (P2), born of consanguineous Turkish parents, with congenital disorder of glycosylation type IIl (CDG2L; 614576), Rymen et al. (2015) identified a homozygous intronic T-to-G transversion (c.1746+2T-G, NM_001145079) in the COG6 gene, resulting in a splice defect. An unrelated patient (P6.1) of Turkish origin was compound heterozygous for the splice site mutation and R171X (606977.0003). Functional studies of the variants and studies of patient cells were not performed, but the variants were predicted to result in a loss of function. (In the article by Rymen et al. (2015), this mutation is variably stated as c.1746+2T-G and c.1746+2G-T.)
In 2 brothers (P4.1 and P4.2), reportedly cousins of the patient described by Lubbehusen et al. (2010) and stated to be born of unrelated Moroccan parents, with congenital disorder of glycosylation type IIl (CDG2L; 614576), Rymen et al. (2015) identified compound heterozygous mutations in the COG6 gene: a c.785A-G transition (c.785A-G, NM_001145079) in exon 8, resulting in a tyr262-to-cys (Y262C) substitution, and G549R (606977.0001). Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function.
In a female infant (P3), born of consanguineous Turkish parents, with congenital disorder of glycosylation type IIl (CDG2L; 614576), Rymen et al. (2015) identified a homozygous 1-bp insertion (c.1238_1239insA, NM_001145079) in the COG6 gene, predicted to result in a frameshift and premature termination (Phe414LeufsTer4). Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function.
Alkuraya, F. S., Shaheen, R. Variable phenotypic expression of COG6 mutation. The Authors' Reply. (Letter) J. Med. Genet. 51: 425-426, 2014. [PubMed: 24667118] [Full Text: https://doi.org/10.1136/jmedgenet-2014-102388]
Haijes, H., Prinsen, H. C. M. T., Thiel, C., Koerner, C., Verhoeven-Duif, N. M., van Hasselt, P. M. Expanding the clinical phenotype of COG6 deficiency. (Letter) J. Med. Genet. 51: 425 only, 2014. [PubMed: 24667119] [Full Text: https://doi.org/10.1136/jmedgenet-2014-102329]
Hirosawa, M., Nagase, T., Ishikawa, K., Kikuno, R., Nomura, N., Ohara, O. Characterization of cDNA clones selected by the GeneMark analysis from size-fractionated cDNA libraries from human brain. DNA Res. 6: 329-336, 1999. [PubMed: 10574461] [Full Text: https://doi.org/10.1093/dnares/6.5.329]
Huybrechts, S., De Laet, C., Bontems, P., Rooze, S., Souayah, H., Sznajer, Y., Sturiale, L., Garozzo, D., Matthijs, G., Ferster, A., Jaeken, J., Goyens, P. Deficiency of subunit 6 of the conserved oligomeric Golgi complex (COG6-CDG): second patient, different phenotype. JIMD Rep. 4: 103-108, 2012. [PubMed: 23430903] [Full Text: https://doi.org/10.1007/8904_2011_79]
Lubbehusen, J., Thiel, C., Rind, N., Ungar, D., Prinsen, B. H. C. M. T., de Koning, T. J., van Hasselt, P. M., Korner, C. Fatal outcome due to deficiency of subunit 6 of the conserved oligomeric Golgi complex leading to a new type of congenital disorders of glycosylation. Hum. Molec. Genet. 19: 3623-3633, 2010. [PubMed: 20605848] [Full Text: https://doi.org/10.1093/hmg/ddq278]
Rymen, D., Winter, J., Van Hasselt, P. M., Jaeken, J., Kasapkara, C., Gokcay, G., Haijes, H., Goyens, P., Tokatli, A., Thiel, C., Bartsch, O., Hecht, J., Krawitz, P., Prinsen, H. C. M. T., Mildenberger, E., Matthijs, G., Kornak, U. Key features and clinical variability of COG6-CDG. Molec. Genet. Metab. 116: 163-170, 2015. [PubMed: 26260076] [Full Text: https://doi.org/10.1016/j.ymgme.2015.07.003]
Shaheen, R., Ansari, S., Alshammari, M. J., Alkhalidi, H., Alrukban, H., Eyaid, W., Alkuraya, F. S. A novel syndrome of hypohidrosis and intellectual disability is linked to COG6 deficiency. J. Med. Genet. 50: 431-436, 2013. [PubMed: 23606727] [Full Text: https://doi.org/10.1136/jmedgenet-2013-101527]
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]