ClinVar

In 5 sibs, born of consanguineous Omani parents, with immunodeficiency-128 (IMD128; 620983), Bainter et al. (2021) identified a homozygous c.1954A-G transition in the COPG1 gene, resulting in a lys652-to-glu (K652E) substitution at a highly conserved residue at the N-terminal end of the appendage domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was heterozygous in the unaffected parents. It was not present in the 1000 Genomes Project or ExAC databases. Immunoblot analysis of patient fibroblasts showed expression levels of the mutant protein comparable to controls, and coimmunoprecipitation studies suggested that mutant COPG1 integrated normally into the COPI complex. Patient fibroblasts showed impaired retrograde COPI transport compared to controls, as evidenced by increased KDELR1 (131235) localization to the Golgi; direct binding of the mutant COPG1 coatomer to KDELR1 was disrupted by the K652E mutation. Binding to ARFGAP1 (608377) was retained and may have compensated for the defect. Vesicle formation was unaffected. Similar defects were observed in embryonic fibroblasts from mutant mice expressing the K652E mutation (see ANIMAL MODEL). Overall, the findings suggested that impaired retrieval of KDEL-bearing chaperones to the ER causes exaggerated ER stress in activated B and T cells.