A Novel Immunodeficiency Due to a Mutation in the γ1-COP Subunit of the COPI Coatomer

Abstract

COPI-mediated retrograde trafficking is responsible for the retrieval of endoplasmic reticulum (ER) resident chaperones that escape to the cis-Golgi. ER resident chaperones with a C-terminal KDEL motif bind to the KDELR and are transported from the Golgi to the ER via COPI. Failure of this retrieval results in the accumulation of unfolded nascent proteins in the ER causing ER stress. T and B cells are particularly prone to ER stress during infection as they are stimulated to produce large quantities of cytokines and antibodies, respectively. We describe an Omani family with increased susceptibility to viral infections and pneumonia due to encapsulated bacteria associated with CD4+ T cell lymphopenia and hypogammaglobulinemia. Whole exome sequencing identified a bi-allelic missense mutation (K652E) in the γ1-COP subunit of the heptameric COPI coatomer. Patient fibroblasts had impaired retrograde trafficking from the cis-Golgi to ER and diminished co-localization of COPI with the KDEL receptor (KDLER). Copg1K652E mice had severely reduced serum IgG levels and impaired T-cell dependent and T cell-independent antibody responses. Mutant B cells displayed increased ER stress and reduced immunoglobulin secretion, which could be rescued by the chemical chaperone TUDCA. Chronically stimulated Copg1K652E T cells demonstrated impaired survival and cytokine secretion. This study identifies the first human disease caused by a mutation in COPG1, revealing a previously unknown role of intracellular protein trafficking and ER stress in adaptive immunity.