Alternative titles; symbols
HGNC Approved Gene Symbol: COPB1
Cytogenetic location: 11p15.2 Genomic coordinates (GRCh38): 11:14,457,512-14,499,811 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p15.2 | Baralle-Macken syndrome | 619255 | Autosomal recessive | 3 |
The Golgi complex is a key organelle where processing and sorting of newly synthesized proteins occurs. Membrane traffic from the endoplasmic reticulum (ER) to the Golgi complex and from the Golgi complex to the different final cellular destinations is believed to be mediated by carrier vesicles (Palade, 1975). Beta-COP is involved in protein transport between the ER and the Golgi complex (summary by Duden et al., 1991).
Duden et al. (1991) cloned the rat liver Golgi complex-associated 110-kD protein, which they called beta-Cop (for coat protein). It is a peripheral Golgi membrane protein that shows significant homology to beta-adaptin (600157). It is present in a membrane-bound form and in a cytosolic complex of 13-14S.
Benichou et al. (1994) determined that the amino acid sequences of the human and rat beta-COP C-terminal domains are over 95% conserved. By Northern blot analysis, they found that human beta-COP is expressed as a 3.2-kb mRNA.
Using the yeast 2-hybrid system, Benichou et al. (1994) found that the C-terminal region of human beta-COP interacts with the HIV-1 Nef protein.
In 6 girls from 2 unrelated consanguineous families with Baralle-Macken syndrome (BARMACS; 619255), Macken et al. (2021) identified 2 different homozygous mutations in the COPB1 gene, a splice site mutation (600959.0001 and a missense 600959.0002) mutation. The mutations, which were found by whole-exome or whole-genome sequencing, segregated with the disorder in the families. Neither was present in the gnomAD database. In vitro functional studies of the mutations suggested that the variants are hypomorphic.
Macken et al. (2021) found that CRISPR/Cas9-mediated disruption of the copb1 gene in X. tropicalis caused microcephaly, cataracts, and occasional anophthalmia in mutant animals. Some animals showed mild forebrain abnormalities.
In 2 teenaged sisters, born of consanguineous Roma Polish parents, with Baralle-Macken syndrome (BARMACS; 619255), Macken et al. (2021) identified a homozygous G-to-T transversion (c.957+1G-T, NM_016451.4) at the +1 position of the splice donor site of exon 8 of the COPB1 gene. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. PCR analysis of patient cells showed that the mutation resulted in 2 mutant transcripts: one that skipped exon 8 and caused an in-frame deletion of 36 residues, and another that included exon 8 with a 1-bp deletion of c.958G, leading to premature termination 18 bp downstream. The mutant transcripts appeared to escape nonsense-mediated mRNA decay.
In 4 female members of a consanguineous Saudi family (family 2) with Baralle-Macken syndrome (BARMACS; 619255), Macken et al. (2021) identified a homozygous c.1651T-G transversion (c.1651T-G, NM_016451.4) in exon 14 of the COPB1 gene, resulting in a phe551-to-val (F551V) substitution at a highly conserved residue in the beta-COP trunk domain. The mutation, which was found by whole-genome sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Molecular modeling suggested that the mutation may impair the structural integrity of beta-COP. Transfection of the mutation into HEK293 cells resulted in a mild decrease in mutant protein levels, suggesting instability. Transfection of the mutation into retinal RPE cells showed diffuse localization of the mutant protein compared to wildtype, which was seen in a defined pattern at the Golgi. The authors concluded that these findings represent defective Golgi to ER endosomal recycling, with mutant beta-COP being abnormally retained in the Golgi.
Benichou, S., Bomsel, M., Bodeus, M., Durand, H., Doute, M., Letourneur, F., Camonis, J., Benarous, R. Physical interaction of the HIV-1 Nef protein with beta-COP, a component of non-clathrin-coated vesicles essential for membrane traffic. J. Biol. Chem. 269: 30073-30076, 1994. [PubMed: 7982906]
Duden, R., Griffiths, G., Frank, R., Argos, P., Kreis, T. E. Beta-COP, a 110 kd protein associated with non-clathrin-coated vesicles and the Golgi complex, shows homology to beta-adaptin. Cell 64: 649-665, 1991. [PubMed: 1840503] [Full Text: https://doi.org/10.1016/0092-8674(91)90248-w]
Macken, W., Godwin, A., Wheway, G., Stals, K., Nazlamova, L., Ellard, S., Alfares, A., Aloraini, T., AlSubaie, L., Alfadhel, M., Alajaji, S., Wai, H. A., Self, J., Douglas, A. G. L., Kao, A. P., Guille, M., Baralle, D. Biallelic variants in COPB1 cause a novel, severe intellectual disability syndrome with cataracts and variable microcephaly. Genome Med. 13: 34, 2021. [PubMed: 33632302] [Full Text: https://doi.org/10.1186/s13073-021-00850-w]
Palade, G. Intracellular aspects of the process of protein synthesis. Science 189: 347-358, 1975. [PubMed: 1096303] [Full Text: https://doi.org/10.1126/science.1096303]