Submission Details

COPG1 was been reported in relation to an autosomal recessive combined immunodeficiency due to COPG1 deficiency by Bainter W et al. in 2021 (PMID: 33529166). To date, this is the only report of the disease. This publication reports the case of 5 siblings from the same consanguineous family, all homozygous for the same missense mutation. This disease is characterize by onset of recurrent respiratory infections, failure to thrive and severe CD4+ T cell lymphopenia in early childhood. All 5 patients had multiple bacterial and viral infections, both in sputum and blood, and diminished IgG in response to stimulation with anti-CD40+IL-4 but surprisingly no reports of autoinflammation. There were no reported symptoms in the heterozygous parents. The curation of COPG1 related to autosomal recessive combined immunodeficiency due to COPG1 deficiency had MONDO ID 0800136 and includes both case-level and experimental-level data. A score of 1.5 points for genetic evidence has been reached. This gene-disease association is also supported by protein interaction, animal model, cell culture model and functional alteration evidence (PMID: 33529166, 35484149 and 22304919). A mouse model with the same homozygous mutation as the patients was created and researchers found the mouse embryonic fibroblasts with the mutated Copg1 exhibited defective retrograde COPI transport similar to that seen in cells derived from affected patients. Also, activated B cells from Copg1 mutant mice have mislocalized ER chaperones and increased ER stress. The same mutated mice co-housed with pet stored mice exhibited reduced number of CD3+, CD4+ and CD8+ T cells, reduced anti-CD3+anti-CD28 driven T cell proliferation and reduced number of B cells (when compared to controls). A cell culture model had COPG1 gene deleted from HeLa cells and an accumulation of KDEL in the Golgi due to defective retrograde trafficking was observed. These cells showed a significant shift in KDEL localization towards the Golgi compartments when compared to controls. THP-1 cells had COPG1 deleted and this showed that the cGAS/STING pathway is activated upon deletion of COPG1, inducing inflammatory signaling. They also observed a significant increase of inflammatory cytokines when compared to parent cells. Finally, anchor protein Arf1-GTP, in the presence of GAP, is hydrolyzed 20 times faster when bound to tetramer βδ/γζ-COP. A score of 5 points for experimental evidence has been reached, increasing the total score to 6.5 points. In summary, COPG1 is moderately associated with autosomal recessive non-severe combined immunodeficiency due to COPG1 deficiency. More cases and research will be needed to elevate the classification to strong. This classification was approved by the ClinGen SCID/CID GCEP on the meeting date January 18, 2024 (SOP Version 10).