Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex

Bainter, Wayne; Platt, Craig D.; Park, Seung-Yeol; Stafstrom, Kelsey; Wallace, Jacqueline G.; Peters, Zachary; Massaad, Michel J.; Salinas, Sandra Andrea; Jones, Jennifer; Beaussant-Cohen, Sarah; Jaber, Faris; Yang, Jia‐Shu; Walther, Tobias C.; Orange, Jordan S.; Rao, Chitong; Rakoff-Nahoum, Seth; Tsokos, Maria; Naseem, Shafiq Ur Rehman; Al‐Tamemi, Salem; Chou, Janet; Hsu, Victor; Geha, Raif S.

doi:10.1172/jci140494

Cited by 15 publications

(15 citation statements)

References 53 publications

(69 reference statements)

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“…PAX1 [13,14], ITPKB [15]; SASH3 [16,17], MAN2B2 [18], COPG1 [19], IKZF2 [20][21][22][23], CHUK [24], IKZF3 [25,26], CRACR2A [27], CD28 [28]) (Table 1; Supplementary Table 1); • Combined immunodeficiencies with syndromic features (MCM10 [29,30], IL6ST [31][32][33], DIAPH1 [34]) (Table 2; Supplementary Table 1); • B cell deficiencies, agammaglobulinemia, or hypogammaglobulinemia (FNIP1 [35,36], SP1I [37], PIK3CG [38,39], POU2AF1 [40], CTNNBL1 [41], TNSRSF13 [42]) (Table 3; Supplementary Table 1); • Immune dysregulation (RHOG [43], SOCS1 [44][45][46],…”

Section: Novel Inborn Errors Of Immunitymentioning

confidence: 99%

Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee

et al. 2022

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We report the updated classification of inborn errors of immunity, compiled by the International Union of Immunological Societies Expert Committee. This report documents the key clinical and laboratory features of 55 novel monogenic gene defects, and 1 phenocopy due to autoantibodies, that have either been discovered since the previous update (published January 2020) or were characterized earlier but have since been confirmed or expanded in subsequent studies. While variants in additional genes associated with immune diseases have been reported in the literature, this update includes only those that the committee assessed that reached the necessary threshold to represent novel inborn errors of immunity. There are now a total of 485 inborn errors of immunity. These advances in discovering the genetic causes of human immune diseases continue to significantly further our understanding of molecular, cellular, and immunological mechanisms of disease pathogenesis, thereby simultaneously enhancing immunological knowledge and improving patient diagnosis and management. This report is designed to serve as a resource for immunologists and geneticists pursuing the molecular diagnosis of individuals with heritable immunological disorders and for the scientific dissection of cellular and molecular mechanisms underlying monogenic and related human immune diseases.

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Section: Novel Inborn Errors Of Immunitymentioning

confidence: 99%

Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee

et al. 2022

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“…A recent paper [ 19 ] reports that homozygous missense mutation p.K652E in human γ1-COP impedes on the ability of COPI complex to bind to the KDEL receptor (KDELR), a key step in the retrieval of chaperones containing the KDEL domain from Golgi to endoplasmic reticulum (ER). The KDEL chaperone proteins are required in ER to assist the proper folding of the secretory proteins as antibodies and cytokines, and their absence contributes to ER stress.…”

Section: Discussionmentioning

confidence: 99%

“…Purportedly, the prognostic of some bacterial infections should be estimated not only by the classical clinical procedures, but also by a quick screening of patients for γCOP mutations, as inferred from recent medical research data [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

“…The main such processes are: the production of inflammatory cytokines, trimming of peptide ligands and assembling of the major histocompatibility complex (MHC) class I molecules, and the transport of both MHC class I and class II complexes to the cell surface [ 15 , 16 , 17 , 18 ]. Moreover, γCOP is important for the ER homeostasis and hence for the innate immunity, but also for the adaptive immunity as revealed in humans [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

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Mutations of γCOP Gene Disturb Drosophila melanogaster Innate Immune Response to Pseudomonas aeruginosa

Chifiriuc

Bologa

Rațiu

et al. 2022

IJMS

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Drosophila melanogaster (the fruit fly) is a valuable experimental platform for modeling host–pathogen interactions. It is also commonly used to define innate immunity pathways and to understand the mechanisms of both host tolerance to commensal microbiota and response to pathogenic agents. Herein, we investigate how the host response to bacterial infection is mirrored in the expression of genes of Imd and Toll pathways when D. melanogaster strains with different γCOP genetic backgrounds are infected with Pseudomonas aeruginosa ATCC 27853. Using microarray technology, we have interrogated the whole-body transcriptome of infected versus uninfected fruit fly males with three specific genotypes, namely wild-type Oregon, γCOPS057302/TM6B and γCOP14a/γCOP14a. While the expression of genes pertaining to Imd and Toll is not significantly modulated by P. aeruginosa infection in Oregon males, many of the components of these cascades are up or downregulated in both infected and uninfected γCOPS057302/TM6B and γCOP14a/γCOP14a males. Thus, our results suggest that a γCOP genetic background modulates the gene expression profiles of Imd and Toll cascades involved in the innate immune response of D. melanogaster, inducing the occurrence of immunological dysfunctions in γCOP mutants.

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“…The importance of KDELR1 in the immune response is also supported by mutations in the membrane trafficking partners of KDELRs. Homozygous mutation in the γ1 subunit of coat protein complex I (COPI; γ1-COP) that disrupts the binding of COPI to KDELRs impairs the retro-translocation of KDEL-bearing chaperones and causes combined immunodeficiency (CID) characterized by defective innate and adaptive immunity [ 71 ].…”

Section: Involvement Of Kdelrs In Human Diseasesmentioning

confidence: 99%

KDEL Receptors: Pathophysiological Functions, Therapeutic Options, and Biotechnological Opportunities

et al. 2022

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KDEL receptors (KDELRs) are ubiquitous seven-transmembrane domain proteins encoded by three mammalian genes. They bind to and retro-transport endoplasmic reticulum (ER)-resident proteins with a C-terminal Lys-Asp-Glu-Leu (KDEL) sequence or variants thereof. In doing this, KDELR participates in the ER quality control of newly synthesized proteins and the unfolded protein response. The binding of KDEL proteins to KDELR initiates signaling cascades involving three alpha subunits of heterotrimeric G proteins, Src family kinases, protein kinases A (PKAs), and mitogen-activated protein kinases (MAPKs). These signaling pathways coordinate membrane trafficking flows between secretory compartments and control the degradation of the extracellular matrix (ECM), an important step in cancer progression. Considering the basic cellular functions performed by KDELRs, their association with various diseases is not surprising. KDELR mutants unable to bind the collagen-specific chaperon heat-shock protein 47 (HSP47) cause the osteogenesis imperfecta. Moreover, the overexpression of KDELRs appears to be linked to neurodegenerative diseases that share pathological ER-stress and activation of the unfolded protein response (UPR). Even immune function requires a functional KDELR1, as its mutants reduce the number of T lymphocytes and impair antiviral immunity. Several studies have also brought to light the exploitation of the shuttle activity of KDELR during the intoxication and maturation/exit of viral particles. Based on the above, KDELRs can be considered potential targets for the development of novel therapeutic strategies for a variety of diseases involving proteostasis disruption, cancer progression, and infectious disease. However, no drugs targeting KDELR functions are available to date; rather, KDELR has been leveraged to deliver drugs efficiently into cells or improve antigen presentation.

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Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex

Cited by 15 publications

References 53 publications

Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee

Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee

Mutations of γCOP Gene Disturb Drosophila melanogaster Innate Immune Response to Pseudomonas aeruginosa

KDEL Receptors: Pathophysiological Functions, Therapeutic Options, and Biotechnological Opportunities

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