Immunodeficiency 128

Mendelian MONDO:0975834 Pathograph 20 Show in embeddings browser hereditary disease inborn error of immunity primary immunodeficiency disease combined immunodeficiency

Immunodeficiency-128 (IMD128) is an autosomal recessive combined immunodeficiency caused by biallelic variants in COPG1, which encodes the gamma-1 subunit of the coat protein I (COPI) coatomer. It is known from a single consanguineous Omani kindred of five affected siblings homozygous for the missense allele p.K652E. The mechanism is a trafficking defect rather than a defect in an immune effector: the substitution disrupts binding of the COPI coat to the KDEL receptor, so KDEL-bearing endoplasmic reticulum chaperones are not retrieved from the Golgi back to the ER. The consequence falls on cells that depend on a large secretory load. In the knock-in mouse, activated T and B cells accumulate ER stress, antibody responses are poor, and activated T cells undergo increased apoptosis despite normal resting T cell numbers and proliferation. Clinically the siblings had persistent bacterial and viral infections with defective humoral and cellular immunity, presenting in infancy with recurrent pulmonary infections, failure to thrive, and persistent EBV and CMV viremia. The entry is deliberately thin: the disease rests on one published family, there is no prevalence estimate, no clinical trial, and no GeneReviews chapter.

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1
Mappings
1
Inheritance
7
Pathophys.
10
Phenotypes
3
Gaps
20
Pathograph
1
Genes
1
Medical Actions
2
Differentials
2
Models
4
References
1
Deep Research
🏷

Classifications

IUIS Category
combined immunodeficiency
🔗

Mappings

MONDO
MONDO:0800136 non-severe combined immunodeficiency due to COPG1 deficiency
skos:exactMatch MONDO
MONDO has scheduled MONDO:0975834 for merger into MONDO:0800136 on the grounds that the two terms denote the same concept, so the successor term is recorded here as an exact match. MONDO:0975834 was still live and not obsolete at the time of curation, and it is the identifier the entry is keyed on; if the merge completes, the primary disease_term should be repointed to MONDO:0800136.
👪

Inheritance

1
Autosomal recessive HP:0000007
All five affected siblings in the single reported kindred were homozygous for the same COPG1 missense allele, and their parents were consanguineous. The entry does not state a recurrence risk figure because the source reports the genotypes rather than a counselling estimate.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:33529166 SUPPORT Human Clinical
"Five siblings with persistent bacterial and viral infections and defective humoral and cellular immunity had a homozygous p.K652E mutation"
Homozygosity in five affected siblings of one sibship establishes recessive inheritance of the COPG1 allele.
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Discussions and Knowledge Gaps

3
What is the standard of care for a child with COPG1 deficiency, and does immunoglobulin replacement, antimicrobial prophylaxis or haematopoietic stem cell transplantation change outcome?
KNOWLEDGE GAP copg1_human_treatment_absent
Attached to
treatments#
No management recommendation could be sourced for this disorder during curation. The only reported therapeutic result is correction of the mouse phenotype by tauroursodeoxycholic acid. Because the mechanism is a cell-intrinsic trafficking defect present in every cell, whether a haematopoietic graft would be curative is not obvious and has not been reported.
Does the cGAS/STING-driven type I interferon activation seen in COPG1-deleted cell lines occur in patients carrying the p.K652E missense allele, and if so does it contribute to their disease?
KNOWLEDGE GAP copg1_type_i_interferon_in_patients
Attached to
pathophysiology#Impaired Retrieval of KDEL-Bearing Chaperones to the ER
Complete deletion of COPG1 in HeLa and THP-1 cells activates STING and type I interferon signalling, and the authors explicitly raise the possibility of inflammatory disease from other COPI subunit genes. The reported COPG1 patients are described as infection-prone rather than autoinflammatory, and a missense allele that leaves the subunit in the coat is not the same lesion as a null. No interferon signature has been reported in these patients.
Why does the Copg1 K652E mouse reproduce the patients' lymphopenia and T cell proliferation defect only after exposure to pet store mice, and what does that imply for the human disease?
HUMAN MODEL MISMATCH copg1_mouse_needs_microbial_exposure
Attached to
animal_models#Mouse pathophysiology#Defective Humoral and Cellular Immunity
Under specific-pathogen-free housing the knock-in mouse has normal T cell numbers and normal proliferation, and only acquires the patients' systemic findings once cohoused with pet store mice. The cellular lesion is therefore faithful while the organism-level phenotype is conditional on antigenic burden. If that dependence holds in humans, it would predict that severity tracks cumulative infection exposure rather than genotype alone, which bears directly on whether early prophylaxis is worthwhile. It is untested.
⚙

Pathophysiology

7
Homozygous COPG1 p.K652E Substitution
The five affected siblings carry a homozygous p.K652E missense substitution in COPG1, which encodes the gamma-1 subunit of the COPI coatomer. This is the only COPG1 genotype reported in an immunodeficient patient.
COPG1 hgnc:2236 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves COPG1 (hgnc:2236). hgnc:2236 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context allele_type: missense substitution variant_origin: GERMLINE zygosity: HOMOZYGOUS
Homozygous p.K652E in COPG1, shared by all five affected siblings of a consanguineous sibship.
Downstream
Disrupted COPI Binding to the KDEL Receptor The substitution itself is what abolishes the coat-receptor interaction; no intermediate step is reported between genotype and binding defect.
Show evidence (1 reference)
PMID:33529166 SUPPORT Human Clinical
"homozygous p.K652E mutation in the γ1 subunit of COPI (γ1-COP)"
Identifies the causal genotype as homozygous p.K652E in the gamma-1 COPI subunit.
Disrupted COPI Binding to the KDEL Receptor
The mutant coatomer no longer binds the KDEL receptor, the cargo receptor that captures ER-resident chaperones escaped to the Golgi. COPI itself is the complex that mediates retrograde traffic from Golgi to endoplasmic reticulum, so losing the receptor interaction removes the link between coat and cargo rather than abolishing the coat.
Downstream
Impaired Retrieval of KDEL-Bearing Chaperones to the ER Loss of coat-receptor binding is reported in the same sentence as, and as the cause of, the failure of chaperone retrieval.
Show evidence (1 reference)
PMID:33529166 SUPPORT BACKGROUND Other
"The coat protein I (COPI) complex mediates retrograde trafficking from the Golgi to the endoplasmic reticulum (ER)."
Establishes what the complex carrying the mutant subunit does. Quoted from the paper's framing sentence rather than from its own results, and graded OTHER because the sentence states established cell-biological background rather than any study's evidence.
Impaired Retrieval of KDEL-Bearing Chaperones to the ER
KDEL-bearing ER chaperones that have escaped to the Golgi are not returned, depleting the ER of the folding capacity it needs when secretory demand rises.
retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum GO:0006890 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum (GO:0006890). GO:0006890 is a biological process from the Gene Ontology. ↓ DECREASED
Experimental models
CRISPR/Cas9 COPG1-deficient HeLa and THP-1 cell lines CELL LINE Deleting COPG1 reproduces the retrograde-trafficking defect, measured as KDEL signal redistributing onto the cis-Golgi.
Downstream
Endoplasmic Reticulum Stress in Activated Lymphocytes The knock-in mouse shows that the retrieval defect is expressed as ER stress specifically in lymphocytes that have been activated, that is, in cells whose secretory load has just increased.
Show evidence (1 reference)
PMID:33529166 SUPPORT In Vitro
"impairs the retrieval of KDEL-bearing chaperones from the Golgi to the ER"
States the trafficking consequence that defines this node.
Endoplasmic Reticulum Stress in Activated Lymphocytes
Activated T and B cells accumulate ER stress. This is the point at which a housekeeping trafficking defect becomes an immune defect, because it is activation, not the resting state, that raises the folding load.
activated T cell CL:0000084 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves activated T cell, annotated with T cell (CL:0000084). CL:0000084 is a cell type from the Cell Ontology. activated B cell CL:0000236 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves activated B cell, annotated with B cell (CL:0000236). CL:0000236 is a cell type from the Cell Ontology.
endoplasmic reticulum unfolded protein response GO:0030968 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased endoplasmic reticulum unfolded protein response (GO:0030968). GO:0030968 is a biological process from the Gene Ontology. ↑ INCREASED
Animal models
Copg1 K652E knock-in mouse Mouse recapitulates The knock-in carries the patients' exact substitution and reproduces the ER stress in activated T and B cells.
Downstream
Increased Apoptosis of Activated T Cells In the knock-in mouse, T cells are present in normal numbers and proliferate normally but die on activation, which is the same conditional pattern as the ER stress.
Poor Antibody Responses Antibody responses are poor in the same animals in which activated B cells carry increased ER stress.
Show evidence (1 reference)
PMID:33529166 SUPPORT Model Organism
"increased ER stress in activated T and B cells"
Locates the ER stress in activated lymphocytes of both lineages.
Increased Apoptosis of Activated T Cells
T cells die when activated rather than failing to develop. That distinction matters clinically: it predicts preserved or near-preserved resting T cell numbers with a functional defect that appears only under demand, which is the pattern of a non-severe combined immunodeficiency rather than of SCID.
activated T cell CL:0000084 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves activated T cell, annotated with T cell (CL:0000084). CL:0000084 is a cell type from the Cell Ontology.
apoptotic process GO:0006915 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased apoptotic process (GO:0006915). GO:0006915 is a biological process from the Gene Ontology. ↑ INCREASED
Animal models
Copg1 K652E knock-in mouse Mouse recapitulates T cells are present in normal numbers and proliferate normally but die on activation.
Downstream
Defective Humoral and Cellular Immunity Loss of activated T cells is the cellular arm of the combined defect reported in the patients.
Abnormal T cell proliferation Impaired T cell proliferation is the laboratory reading of the same activation-dependent defect. The steps between the two are not established: in specific-pathogen-free mutant mice the T cells undergo increased apoptosis while proliferating normally, and the proliferation defect emerges only after microbial exposure, so the reported data do not show apoptosis producing the proliferation failure.
Show evidence (1 reference)
PMID:33529166 SUPPORT Model Organism
"underwent increased apoptosis upon activation"
States the activation-conditional apoptosis defining this node.
Poor Antibody Responses
The humoral arm of the defect. In the mouse it is measured as a poor antibody response; in the patients it appears as poor specific antibody responses.
Downstream
Defective Humoral and Cellular Immunity Failure to mount antibody is the humoral arm of the combined defect.
Impaired specific antibody response The patients' poor specific antibody responses are the clinical expression of this node.
Show evidence (1 reference)
PMID:33529166 SUPPORT Model Organism
"Homozygous Copg1K652E mice had increased ER stress in activated T and B cells, poor antibody responses"
Reports the impaired antibody response in the knock-in mouse.
Defective Humoral and Cellular Immunity
The combined immune defect as it presents clinically: both the antibody and the T cell arms are affected, which is what makes this a combined rather than a predominantly antibody deficiency.
Animal models
Copg1 K652E knock-in mouse Mouse partially recapitulates The organism-level phenotype appears only under microbial exposure: after cohousing with pet store mice the mutants lost weight and developed lymphopenia and defective T cell proliferation resembling the patients.
Downstream
Recurrent bacterial infections Failure of both immune arms permits persistent bacterial infection.
Recurrent viral infections Failure of cellular immunity permits persistent viral infection.
Recurrent lower respiratory tract infections The lung is the dominant site of infection in the reported patients, who presented with recurrent pulmonary infection.
Persistent CMV viremia Failure to clear CMV is a specific expression of the cellular defect.
Persistent EBV viremia Failure to control EBV is a specific expression of the cellular defect.
Failure to thrive Growth failure accompanies the infection burden in the reported patients. The source lists it beside the infections without establishing the mechanism, so the intermediate steps are not recorded here.
Decreased total CD4+ T cell count Severe CD4+ lymphopenia is the quantitative laboratory correlate of the cellular arm of the defect in the reported patients.
Show evidence (1 reference)
PMID:33529166 SUPPORT Human Clinical
"defective humoral and cellular immunity"
States the combined nature of the immune defect in the patients.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Immunodeficiency 128 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

10
Blood 2
Decreased total CD4+ T cell count HP:5210418 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Severe CD4+ lymphopenia, annotated with Decreased total CD4+ T cell count (HP:5210418). HP:5210418 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41676145 SUPPORT BACKGROUND Human Clinical
"Immunological characteristics include severe CD4+ lymphopenia, poor specific antibody responses, and impaired T-cell proliferation"
States the CD4+ lymphopenia reported in the COPG1 patients.
Abnormal T cell proliferation HP:0031379 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Impaired T-cell proliferation, annotated with Abnormal T cell proliferation (HP:0031379). HP:0031379 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41676145 SUPPORT BACKGROUND Human Clinical
"Immunological characteristics include severe CD4+ lymphopenia, poor specific antibody responses, and impaired T-cell proliferation"
States the impaired T cell proliferation reported in the COPG1 patients.
Immune 7
Combined immunodeficiency HP:0005387 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Combined immunodeficiency (HP:0005387). HP:0005387 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33529166 SUPPORT Human Clinical
"defective humoral and cellular immunity"
Reports involvement of both immune arms in the affected siblings.
Recurrent bacterial infections HP:0002718 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent bacterial infections (HP:0002718). HP:0002718 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33529166 SUPPORT Human Clinical
"Five siblings with persistent bacterial and viral infections"
Reports persistent bacterial infection in the affected siblings.
Recurrent viral infections HP:0004429 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent viral infections (HP:0004429). HP:0004429 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33529166 SUPPORT Human Clinical
"persistent bacterial and viral infections"
Reports persistent viral infection in the affected siblings.
Recurrent lower respiratory tract infections HP:0002783 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent pulmonary infections, annotated with Recurrent lower respiratory tract infections (HP:0002783). HP:0002783 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41676145 SUPPORT BACKGROUND Human Clinical
"Patients with COPG1 deficiency present with recurrent pulmonary infections"
States the presenting infection. Quoted from the introduction of a COPB1 report, where it restates the published COPG1 clinical findings.
Persistent CMV viremia HP:0032247 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Persistent CMV viremia (HP:0032247). HP:0032247 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41676145 SUPPORT BACKGROUND Human Clinical
"susceptibility to persistent EBV and CMV viremia"
Names persistent CMV viremia among the reported COPG1 findings.
Persistent EBV viremia HP:0020072 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Persistent EBV viremia (HP:0020072). HP:0020072 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41676145 SUPPORT BACKGROUND Human Clinical
"susceptibility to persistent EBV and CMV viremia"
Names persistent EBV viremia among the reported COPG1 findings.
Impaired specific antibody response HP:0012475 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Poor specific antibody responses, annotated with Impaired specific antibody response (HP:0012475). HP:0012475 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41676145 SUPPORT BACKGROUND Human Clinical
"Immunological characteristics include severe CD4+ lymphopenia, poor specific antibody responses, and impaired T-cell proliferation"
States the impaired specific antibody responses reported in the COPG1 patients.
Growth 1
Failure to thrive HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41676145 SUPPORT BACKGROUND Human Clinical
"recurrent pulmonary infections, failure to thrive"
Names failure to thrive among the reported COPG1 findings.
🧬

Genetic Associations

1
COPG1
Gene: COPG1 hgnc:2236 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is COPG1 (hgnc:2236). hgnc:2236 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Autosomal recessive
Show evidence (2 references)
PMID:33529166 SUPPORT Human Clinical
"homozygous p.K652E mutation in the γ1 subunit of COPI (γ1-COP)"
Identifies COPG1 (gamma-1 COP) as the mutated gene in the affected siblings.
PMID:41676145 SUPPORT BACKGROUND Human Clinical
"Mutations in COPG1 have been reported as a cause of combined immunodeficiency"
Independent restatement that COPG1 causes combined immunodeficiency. Quoted from the introduction of a COPB1 report rather than from its own results.
💊

Medical Actions

1
Tauroursodeoxycholic acid (preclinical only)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: tauroursodeoxycholic acid CHEBI:80774 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses tauroursodeoxycholic acid (CHEBI:80774). CHEBI:80774 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
The ER stress-relieving bile acid corrected the immune defects of the knock-in mice and reversed the phenotype the mutants acquired after pet store mouse exposure. This is a mouse result. No patient has been reported to receive it for this disorder, no dose or schedule is established, and it is recorded here because it identifies the mechanistic node that is druggable, not because it is a recommended therapy.
Mechanism Target:
Endoplasmic Reticulum Stress in Activated Lymphocytes — The agent acts on the ER stress node rather than on the trafficking defect upstream of it, which is why correction is possible without restoring chaperone retrieval.
Show evidence (1 reference)
PMID:33529166 SUPPORT Model Organism
"The ER stress-relieving agent tauroursodeoxycholic acid corrected the immune defects of the mutants"
Reports correction of the immune defect by an agent acting on ER stress.
Show evidence (1 reference)
PMID:33529166 SUPPORT Model Organism
"tauroursodeoxycholic acid corrected the immune defects of the mutants and reversed the phenotype they acquired following exposure to pet store mice"
The only therapeutic result reported for this disorder, and it is in the mouse.
🔬

Diagnosis

1
Molecular genetic testing for biallelic COPG1 variants
There is no functional screening assay in clinical use. The diagnosis is made by finding a biallelic COPG1 variant in a child with combined immunodeficiency, CD4+ lymphopenia and poor specific antibody responses. Because the disorder is known from a single kindred, a novel COPG1 variant found in another family will need functional support, for which the published assay is loss of coatomer binding to the KDEL receptor with failure of chaperone retrieval.
Show evidence (1 reference)
PMID:33529166 SUPPORT In Vitro
"The mutation disrupts COPI binding to the KDEL receptor and impairs the retrieval of KDEL-bearing chaperones from the Golgi to the ER."
Supports the functional-confirmation part of this diagnostic approach only: it names the assays that established pathogenicity of the reported allele, and says nothing about the sequencing step that finds a variant.
📊

Prevalence

1
Worldwide
Cases In Literature Not yet documented
Five affected siblings from one consanguineous Omani kindred are the only reported patients found during curation. No prevalence, incidence or carrier-frequency estimate exists, and Orphanet records no epidemiology for ORPHA:718017, so no rate is given here.
Show evidence (1 reference)
PMID:33529166 SUPPORT Human Clinical
"Five siblings with persistent bacterial and viral infections"
The reported case count on which this record rests.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Immunodeficiency 128:

COPA syndrome
Overlapping Features The other coatopathy of retrograde Golgi-to-ER transport, and the one a COPG1 patient is most likely to be tested for. COPA syndrome is autosomal dominant and is an interferonopathy driven by cGAS/STING activation, presenting with lung haemorrhage and arthritis rather than with a combined immunodeficiency.
Distinguishing Features
  • COPA syndrome is dominantly inherited; IMD128 is recessive.
  • COPA syndrome presents as autoinflammation and interstitial lung disease rather than as infection susceptibility.
Show evidence (3 references)
PMID:35484149 SUPPORT BACKGROUND Human Clinical
"The disease is caused by autosomal dominant mutations in the COPA gene"
Sources the inheritance half of the distinction. Quoted from the introduction, where it restates the established mode of inheritance of COPA syndrome.
PMID:35484149 SUPPORT BACKGROUND Human Clinical
"including interstitial lung disease with or without pulmonary haemorrhage, inflammatory arthritis, immune-mediated kidney disease and autoantibodies"
Sources the presentation half of the distinction: COPA syndrome presents with inflammatory organ disease rather than with infection susceptibility. Quoted from the introduction.
PMID:35484149 SUPPORT In Vitro
"Genetic deletion of COPI subunits COPG1 or COPD similarly induces type I IFN activation in vitro, which suggests that inflammatory diseases associated with mutations in other COPI subunit genes may exist."
Establishes that the two disorders share a retrograde-transport lesion and that the interferon arm is not unique to COPA, which is why the differential turns on inheritance and presentation rather than on pathway.
COPB1 deficiency
Overlapping Features The beta subunit counterpart. COPB1 deficiency also produces a combined immunodeficiency through the same coatomer, alongside neurological features, so it is a genotype-level rather than a phenotype-level distinction.
Distinguishing Features
  • COPB1 deficiency carries neurological manifestations not reported in the COPG1 kindred.
Show evidence (1 reference)
PMID:41676145 SUPPORT Human Clinical
"This report documents a rare combined immunodeficiency disorder with neurological manifestations"
Establishes COPB1 deficiency as a combined immunodeficiency with neurological features.
🧫

Experimental Models

1
CRISPR/Cas9 COPG1-deficient HeLa and THP-1 cell lines CELL_LINE
Complete deletion of COPG1 in human cell lines, used to ask whether the retrograde-transport lesion of COPA syndrome generalises across COPI subunits. It does: COPG1-null cells show the same shift of KDEL-tagged chaperones towards the Golgi, and they activate cGAS/STING and type I interferon signalling spontaneously.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Publication
PMID:35484149
Pathograph links
Impaired Retrieval of KDEL-Bearing Chaperones to the ER recapitulates fidelity: moderate observes: cellular Deleting COPG1 reproduces the retrograde-trafficking defect, measured as KDEL signal redistributing onto the cis-Golgi.
Limitations: This is a complete null, not the patients' missense allele, and it is a HeLa or THP-1 cell rather than a lymphocyte. The patients' substitution leaves the subunit expressed and incorporated into the coat and disables one interaction, so a deletion may overstate the functional loss and may engage consequences the missense allele does not.
Show evidence (1 reference)
PMID:35484149 SUPPORT In Vitro
"These results indicate that genetic deletion of COPA, COPG1 or COPD results in impaired retrograde trafficking"
Reports the retrograde-trafficking defect measured in COPG1-deleted cells.
Show evidence (1 reference)
PMID:35484149 SUPPORT In Vitro
"only deletion of COPG1 resulted in spontaneous phosphorylation of STAT1 and inflammatory gene transcription"
Reports that COPG1 loss, unlike COPG2 loss, drives spontaneous inflammatory signalling, which is the finding that makes this model relevant beyond the trafficking defect.
🐁

Animal Models

1
Copg1 K652E knock-in mouse
A mouse carrying the patients' substitution. Under specific-pathogen-free conditions it shows the cellular lesion (ER stress in activated lymphocytes, poor antibody responses, activation-induced T cell apoptosis) but normal T cell numbers and proliferation; the patients' proliferation defect and lymphopenia appear only after the animals are exposed to the microbial burden of pet store mice.
Species
Mouse
Genotype
Copg1 K652E homozygous knock-in
Genes
COPG1 hgnc:2236 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns COPG1 (hgnc:2236). hgnc:2236 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:33529166
Pathograph links
Endoplasmic Reticulum Stress in Activated Lymphocytes recapitulates fidelity: high observes: cellular The knock-in carries the patients' exact substitution and reproduces the ER stress in activated T and B cells.
Readouts
ER stress in activated T and B cells
Direction: INCREASED
Interpretation: The cellular lesion the human allele is proposed to cause.
Show evidence (1 reference)
PMID:33529166 SUPPORT Model Organism
"Homozygous Copg1K652E mice had increased ER stress in activated T and B cells"
Reports the measured increase in ER stress in activated lymphocytes.
Show evidence (1 reference)
PMID:33529166 SUPPORT Model Organism
"Homozygous Copg1K652E mice had increased ER stress in activated T and B cells"
Supports treating this knock-in as informative for the ER stress node.
Increased Apoptosis of Activated T Cells recapitulates fidelity: high observes: cellular T cells are present in normal numbers and proliferate normally but die on activation.
Readouts
Apoptosis of T cells upon activation
Direction: INCREASED
Interpretation: Establishes that the defect is conditional on activation rather than developmental.
Show evidence (1 reference)
PMID:33529166 SUPPORT Model Organism
"normal numbers of T cells that proliferated normally, but underwent increased apoptosis upon activation"
Reports the activation-induced apoptosis measurement.
Defective Humoral and Cellular Immunity partially recapitulates fidelity: moderate observes: organism The organism-level phenotype appears only under microbial exposure: after cohousing with pet store mice the mutants lost weight and developed lymphopenia and defective T cell proliferation resembling the patients.
Limitations: Under specific-pathogen-free housing the mutant mice have normal T cell numbers and normal proliferation, so the model reproduces the patients' systemic immune failure only when the environmental antigen burden is raised. The patients' persistent CMV and EBV viremia has no counterpart in the model at all, since neither virus infects mice.
Readouts
Weight, lymphocyte count and T cell proliferation after pet store mouse exposure
Direction: DECREASED
Interpretation: The systemic phenotype that the authors state recapitulates the patients' findings.
Show evidence (1 reference)
PMID:33529166 SUPPORT Model Organism
"Exposure of the mutants to pet store mice caused weight loss, lymphopenia, and defective T cell proliferation that recapitulated the findings in the patients."
Reports the measured systemic phenotype and its dependence on microbial exposure.
Show evidence (1 reference)
PMID:33529166 SUPPORT Model Organism
"Homozygous Copg1K652E mice had increased ER stress in activated T and B cells"
Identifies the genotype of the knock-in model and the lesion it carries.
{ }

Source YAML

click to show 
name: Immunodeficiency 128
creation_date: "2026-09-24T00:00:00Z"
category: Mendelian
description: >-
  Immunodeficiency-128 (IMD128) is an autosomal recessive combined
  immunodeficiency caused by biallelic variants in COPG1, which encodes the
  gamma-1 subunit of the coat protein I (COPI) coatomer. It is known from a
  single consanguineous Omani kindred of five affected siblings homozygous for
  the missense allele p.K652E. The mechanism is a trafficking defect rather
  than a defect in an immune effector: the substitution disrupts binding of the
  COPI coat to the KDEL receptor, so KDEL-bearing endoplasmic reticulum
  chaperones are not retrieved from the Golgi back to the ER. The consequence
  falls on cells that depend on a large secretory load. In the knock-in mouse,
  activated T and B cells accumulate ER stress, antibody responses are poor,
  and activated T cells undergo increased apoptosis despite normal resting T
  cell numbers and proliferation. Clinically the siblings had persistent
  bacterial and viral infections with defective humoral and cellular immunity,
  presenting in infancy with recurrent pulmonary infections, failure to thrive,
  and persistent EBV and CMV viremia. The entry is deliberately thin: the
  disease rests on one published family, there is no prevalence estimate, no
  clinical trial, and no GeneReviews chapter.
parents:
- hereditary disease
- inborn error of immunity
- primary immunodeficiency disease
- combined immunodeficiency

classifications:
  iuis_category:
    classification_value: combined immunodeficiency
    notes: >-
      Defective humoral and cellular immunity together place this with the
      IUIS immunodeficiencies affecting cellular and humoral immunity rather
      than with a predominantly antibody deficiency. The assignment is made
      from the reported phenotype; COPG1 was not listed in the IUIS tables
      consulted during curation, so this is a curator classification and not a
      quoted IUIS entry.

disease_term:
  preferred_term: immunodeficiency 128
  term:
    id: MONDO:0975834
    label: immunodeficiency 128

mappings:
  mondo_mappings:
  - term:
      id: MONDO:0800136
      label: non-severe combined immunodeficiency due to COPG1 deficiency
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO has scheduled MONDO:0975834 for merger into MONDO:0800136 on the
      grounds that the two terms denote the same concept, so the successor term
      is recorded here as an exact match. MONDO:0975834 was still live and not
      obsolete at the time of curation, and it is the identifier the entry is
      keyed on; if the merge completes, the primary disease_term should be
      repointed to MONDO:0800136.

inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    All five affected siblings in the single reported kindred were homozygous
    for the same COPG1 missense allele, and their parents were consanguineous.
    The entry does not state a recurrence risk figure because the source
    reports the genotypes rather than a counselling estimate.
  evidence:
  - reference: PMID:33529166
    reference_title: "Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Five siblings with persistent bacterial and viral infections and defective humoral and cellular immunity had a homozygous p.K652E mutation"
    explanation: Homozygosity in five affected siblings of one sibship establishes recessive inheritance of the COPG1 allele.

pathophysiology:
- name: Homozygous COPG1 p.K652E Substitution
  description: >-
    The five affected siblings carry a homozygous p.K652E missense substitution
    in COPG1, which encodes the gamma-1 subunit of the COPI coatomer. This is
    the only COPG1 genotype reported in an immunodeficient patient.
  biological_scale: MOLECULAR
  genetic_context:
    zygosity: HOMOZYGOUS
    variant_origin: GERMLINE
    allele_type: missense substitution
    description: >-
      Homozygous p.K652E in COPG1, shared by all five affected siblings of a
      consanguineous sibship.
  genes:
  - preferred_term: COPG1
    term:
      id: hgnc:2236
      label: COPG1
  downstream:
  - target: Disrupted COPI Binding to the KDEL Receptor
    causal_link_type: DIRECT
    description: >-
      The substitution itself is what abolishes the coat-receptor interaction;
      no intermediate step is reported between genotype and binding defect.
    evidence:
    - reference: PMID:33529166
      reference_title: "Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The mutation disrupts COPI binding to the KDEL receptor"
      explanation: States that the p.K652E allele is the cause of the lost COPI-KDEL receptor interaction.
  evidence:
  - reference: PMID:33529166
    reference_title: "Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "homozygous p.K652E mutation in the γ1 subunit of COPI (γ1-COP)"
    explanation: Identifies the causal genotype as homozygous p.K652E in the gamma-1 COPI subunit.

- name: Disrupted COPI Binding to the KDEL Receptor
  description: >-
    The mutant coatomer no longer binds the KDEL receptor, the cargo receptor
    that captures ER-resident chaperones escaped to the Golgi. COPI itself is
    the complex that mediates retrograde traffic from Golgi to endoplasmic
    reticulum, so losing the receptor interaction removes the link between coat
    and cargo rather than abolishing the coat.
  biological_scale: MOLECULAR
  downstream:
  - target: Impaired Retrieval of KDEL-Bearing Chaperones to the ER
    causal_link_type: DIRECT
    description: >-
      Loss of coat-receptor binding is reported in the same sentence as, and as
      the cause of, the failure of chaperone retrieval.
    evidence:
    - reference: PMID:33529166
      reference_title: "Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "disrupts COPI binding to the KDEL receptor and impairs the retrieval of KDEL-bearing chaperones from the Golgi to the ER"
      explanation: Directly couples the binding defect to failed chaperone retrieval.
  evidence:
  - reference: PMID:33529166
    reference_title: "Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: OTHER
    snippet: "The coat protein I (COPI) complex mediates retrograde trafficking from the Golgi to the endoplasmic reticulum (ER)."
    explanation: >-
      Establishes what the complex carrying the mutant subunit does. Quoted
      from the paper's framing sentence rather than from its own results, and
      graded OTHER because the sentence states established cell-biological
      background rather than any study's evidence.

- name: Impaired Retrieval of KDEL-Bearing Chaperones to the ER
  description: >-
    KDEL-bearing ER chaperones that have escaped to the Golgi are not returned,
    depleting the ER of the folding capacity it needs when secretory demand
    rises.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum
    term:
      id: GO:0006890
      label: retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum
    modifier: DECREASED
  downstream:
  - target: Endoplasmic Reticulum Stress in Activated Lymphocytes
    causal_link_type: DIRECT
    description: >-
      The knock-in mouse shows that the retrieval defect is expressed as ER
      stress specifically in lymphocytes that have been activated, that is, in
      cells whose secretory load has just increased.
    evidence:
    - reference: PMID:33529166
      reference_title: "Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Homozygous Copg1K652E mice had increased ER stress in activated T and B cells"
      explanation: Reports increased ER stress in activated lymphocytes of mice carrying the patients' allele.
  evidence:
  - reference: PMID:33529166
    reference_title: "Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "impairs the retrieval of KDEL-bearing chaperones from the Golgi to the ER"
    explanation: States the trafficking consequence that defines this node.

- name: Endoplasmic Reticulum Stress in Activated Lymphocytes
  description: >-
    Activated T and B cells accumulate ER stress. This is the point at which a
    housekeeping trafficking defect becomes an immune defect, because it is
    activation, not the resting state, that raises the folding load.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: endoplasmic reticulum unfolded protein response
    term:
      id: GO:0030968
      label: endoplasmic reticulum unfolded protein response
    modifier: INCREASED
  cell_types:
  - preferred_term: activated T cell
    term:
      id: CL:0000084
      label: T cell
  - preferred_term: activated B cell
    term:
      id: CL:0000236
      label: B cell
  downstream:
  - target: Increased Apoptosis of Activated T Cells
    causal_link_type: DIRECT
    description: >-
      In the knock-in mouse, T cells are present in normal numbers and
      proliferate normally but die on activation, which is the same conditional
      pattern as the ER stress.
    evidence:
    - reference: PMID:33529166
      reference_title: "Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "normal numbers of T cells that proliferated normally, but underwent increased apoptosis upon activation"
      explanation: Reports the activation-dependent apoptosis that this edge asserts.
  - target: Poor Antibody Responses
    causal_link_type: DIRECT
    description: >-
      Antibody responses are poor in the same animals in which activated B
      cells carry increased ER stress.
    evidence:
    - reference: PMID:33529166
      reference_title: "Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "increased ER stress in activated T and B cells, poor antibody responses"
      explanation: Reports the poor antibody response alongside the B cell ER stress in the same animals.
  evidence:
  - reference: PMID:33529166
    reference_title: "Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "increased ER stress in activated T and B cells"
    explanation: Locates the ER stress in activated lymphocytes of both lineages.

- name: Increased Apoptosis of Activated T Cells
  description: >-
    T cells die when activated rather than failing to develop. That distinction
    matters clinically: it predicts preserved or near-preserved resting T cell
    numbers with a functional defect that appears only under demand, which is
    the pattern of a non-severe combined immunodeficiency rather than of SCID.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
  cell_types:
  - preferred_term: activated T cell
    term:
      id: CL:0000084
      label: T cell
  downstream:
  - target: Defective Humoral and Cellular Immunity
    causal_link_type: DIRECT
    description: >-
      Loss of activated T cells is the cellular arm of the combined defect
      reported in the patients.
    evidence:
    - reference: PMID:33529166
      reference_title: "Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "defective humoral and cellular immunity"
      explanation: Names the cellular arm of the immune defect that this edge feeds.
  - target: Abnormal T cell proliferation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Impaired T cell proliferation is the laboratory reading of the same
      activation-dependent defect. The steps between the two are not
      established: in specific-pathogen-free mutant mice the T cells undergo
      increased apoptosis while proliferating normally, and the proliferation
      defect emerges only after microbial exposure, so the reported data do not
      show apoptosis producing the proliferation failure.
    evidence:
    - reference: PMID:33529166
      reference_title: "Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Exposure of the mutants to pet store mice caused weight loss, lymphopenia, and defective T cell proliferation that recapitulated the findings in the patients."
      explanation: Reports the proliferation defect and states that it reproduces the patients' finding.
  evidence:
  - reference: PMID:33529166
    reference_title: "Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "underwent increased apoptosis upon activation"
    explanation: States the activation-conditional apoptosis defining this node.

- name: Poor Antibody Responses
  description: >-
    The humoral arm of the defect. In the mouse it is measured as a poor
    antibody response; in the patients it appears as poor specific antibody
    responses.
  biological_scale: ORGANISM
  downstream:
  - target: Defective Humoral and Cellular Immunity
    causal_link_type: DIRECT
    description: >-
      Failure to mount antibody is the humoral arm of the combined defect.
    evidence:
    - reference: PMID:33529166
      reference_title: "Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "persistent bacterial and viral infections and defective humoral and cellular immunity"
      explanation: Names the humoral arm of the immune defect that this edge feeds.
  - target: Impaired specific antibody response
    causal_link_type: DIRECT
    description: >-
      The patients' poor specific antibody responses are the clinical
      expression of this node.
    evidence:
    - reference: PMID:41676145
      reference_title: Expanding the clinical and immunological phenotypes of COPB1 deficiency.
      supports: SUPPORT
      quote_role: BACKGROUND
      evidence_source: HUMAN_CLINICAL
      snippet: "Immunological characteristics include severe CD4+ lymphopenia, poor specific antibody responses, and impaired T-cell proliferation"
      explanation: >-
        States the patients' poor specific antibody responses. Quoted from the
        introduction of a COPB1 report, where it restates the published COPG1
        clinical findings rather than presenting that paper's own results.
  evidence:
  - reference: PMID:33529166
    reference_title: "Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Homozygous Copg1K652E mice had increased ER stress in activated T and B cells, poor antibody responses"
    explanation: Reports the impaired antibody response in the knock-in mouse.

- name: Defective Humoral and Cellular Immunity
  description: >-
    The combined immune defect as it presents clinically: both the antibody and
    the T cell arms are affected, which is what makes this a combined rather
    than a predominantly antibody deficiency.
  biological_scale: ORGANISM
  downstream:
  - target: Recurrent bacterial infections
    causal_link_type: DIRECT
    description: Failure of both immune arms permits persistent bacterial infection.
    evidence:
    - reference: PMID:33529166
      reference_title: "Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Five siblings with persistent bacterial and viral infections and defective humoral and cellular immunity"
      explanation: Reports persistent bacterial infection alongside the combined immune defect in the same patients.
  - target: Recurrent viral infections
    causal_link_type: DIRECT
    description: Failure of cellular immunity permits persistent viral infection.
    evidence:
    - reference: PMID:33529166
      reference_title: "Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "persistent bacterial and viral infections and defective humoral and cellular immunity"
      explanation: Reports persistent viral infection alongside the combined immune defect in the same patients.
  - target: Recurrent lower respiratory tract infections
    causal_link_type: DIRECT
    description: >-
      The lung is the dominant site of infection in the reported patients, who
      presented with recurrent pulmonary infection.
    evidence:
    - reference: PMID:41676145
      reference_title: Expanding the clinical and immunological phenotypes of COPB1 deficiency.
      supports: SUPPORT
      quote_role: BACKGROUND
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients with COPG1 deficiency present with recurrent pulmonary infections, failure to thrive, and susceptibility to persistent EBV and CMV viremia"
      explanation: >-
        States the presenting infection pattern. Quoted from the introduction
        of a COPB1 report restating the published COPG1 findings.
  - target: Persistent CMV viremia
    causal_link_type: DIRECT
    description: Failure to clear CMV is a specific expression of the cellular defect.
    evidence:
    - reference: PMID:41676145
      reference_title: Expanding the clinical and immunological phenotypes of COPB1 deficiency.
      supports: SUPPORT
      quote_role: BACKGROUND
      evidence_source: HUMAN_CLINICAL
      snippet: "susceptibility to persistent EBV and CMV viremia"
      explanation: Names persistent CMV viremia among the reported COPG1 patient findings.
  - target: Persistent EBV viremia
    causal_link_type: DIRECT
    description: Failure to control EBV is a specific expression of the cellular defect.
    evidence:
    - reference: PMID:41676145
      reference_title: Expanding the clinical and immunological phenotypes of COPB1 deficiency.
      supports: SUPPORT
      quote_role: BACKGROUND
      evidence_source: HUMAN_CLINICAL
      snippet: "susceptibility to persistent EBV and CMV viremia"
      explanation: Names persistent EBV viremia among the reported COPG1 patient findings.
  - target: Failure to thrive
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Growth failure accompanies the infection burden in the reported patients.
      The source lists it beside the infections without establishing the
      mechanism, so the intermediate steps are not recorded here.
    evidence:
    - reference: PMID:41676145
      reference_title: Expanding the clinical and immunological phenotypes of COPB1 deficiency.
      supports: SUPPORT
      quote_role: BACKGROUND
      evidence_source: HUMAN_CLINICAL
      snippet: "recurrent pulmonary infections, failure to thrive, and susceptibility to persistent EBV and CMV viremia"
      explanation: Lists failure to thrive among the reported COPG1 patient findings.
  - target: Decreased total CD4+ T cell count
    causal_link_type: DIRECT
    description: >-
      Severe CD4+ lymphopenia is the quantitative laboratory correlate of the
      cellular arm of the defect in the reported patients.
    evidence:
    - reference: PMID:41676145
      reference_title: Expanding the clinical and immunological phenotypes of COPB1 deficiency.
      supports: SUPPORT
      quote_role: BACKGROUND
      evidence_source: HUMAN_CLINICAL
      snippet: "Immunological characteristics include severe CD4+ lymphopenia"
      explanation: States the CD4+ lymphopenia reported in the COPG1 patients.
  evidence:
  - reference: PMID:33529166
    reference_title: "Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "defective humoral and cellular immunity"
    explanation: States the combined nature of the immune defect in the patients.

phenotypes:
- category: Immunologic
  name: Combined immunodeficiency
  description: >-
    Both the antibody and the T cell arms are affected in the reported
    siblings, which is the defining clinical pattern of the disorder.
  phenotype_term:
    preferred_term: Combined immunodeficiency
    term:
      id: HP:0005387
      label: Combined immunodeficiency
  evidence:
  - reference: PMID:33529166
    reference_title: "Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "defective humoral and cellular immunity"
    explanation: Reports involvement of both immune arms in the affected siblings.

- category: Infectious
  name: Recurrent bacterial infections
  description: Persistent bacterial infection in all five reported siblings.
  phenotype_term:
    preferred_term: Recurrent bacterial infections
    term:
      id: HP:0002718
      label: Recurrent bacterial infections
  evidence:
  - reference: PMID:33529166
    reference_title: "Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Five siblings with persistent bacterial and viral infections"
    explanation: Reports persistent bacterial infection in the affected siblings.

- category: Infectious
  name: Recurrent viral infections
  description: Persistent viral infection in all five reported siblings.
  phenotype_term:
    preferred_term: Recurrent viral infections
    term:
      id: HP:0004429
      label: Recurrent viral infections
  evidence:
  - reference: PMID:33529166
    reference_title: "Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "persistent bacterial and viral infections"
    explanation: Reports persistent viral infection in the affected siblings.

- category: Respiratory
  name: Recurrent lower respiratory tract infections
  description: >-
    The presenting complaint. The reported patients present with recurrent
    pulmonary infection, that is, repeated infection of the lung itself.
  phenotype_term:
    preferred_term: Recurrent pulmonary infections
    term:
      id: HP:0002783
      label: Recurrent lower respiratory tract infections
  evidence:
  - reference: PMID:41676145
    reference_title: Expanding the clinical and immunological phenotypes of COPB1 deficiency.
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with COPG1 deficiency present with recurrent pulmonary infections"
    explanation: >-
      States the presenting infection. Quoted from the introduction of a COPB1
      report, where it restates the published COPG1 clinical findings.

- category: Infectious
  name: Persistent CMV viremia
  description: Failure to clear cytomegalovirus, reported in the COPG1 patients.
  phenotype_term:
    preferred_term: Persistent CMV viremia
    term:
      id: HP:0032247
      label: Persistent CMV viremia
  evidence:
  - reference: PMID:41676145
    reference_title: Expanding the clinical and immunological phenotypes of COPB1 deficiency.
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "susceptibility to persistent EBV and CMV viremia"
    explanation: Names persistent CMV viremia among the reported COPG1 findings.

- category: Infectious
  name: Persistent EBV viremia
  description: Failure to control Epstein-Barr virus, reported in the COPG1 patients.
  phenotype_term:
    preferred_term: Persistent EBV viremia
    term:
      id: HP:0020072
      label: Persistent EBV viremia
  evidence:
  - reference: PMID:41676145
    reference_title: Expanding the clinical and immunological phenotypes of COPB1 deficiency.
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "susceptibility to persistent EBV and CMV viremia"
    explanation: Names persistent EBV viremia among the reported COPG1 findings.

- category: Growth
  name: Failure to thrive
  description: >-
    Growth failure accompanies the infection burden. Pediatrically this is the
    feature most likely to bring an affected infant to attention alongside the
    chest infections.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:41676145
    reference_title: Expanding the clinical and immunological phenotypes of COPB1 deficiency.
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "recurrent pulmonary infections, failure to thrive"
    explanation: Names failure to thrive among the reported COPG1 findings.

- category: Laboratory
  name: Decreased total CD4+ T cell count
  description: Severe CD4+ lymphopenia in the reported patients.
  phenotype_term:
    preferred_term: Severe CD4+ lymphopenia
    term:
      id: HP:5210418
      label: Decreased total CD4+ T cell count
  evidence:
  - reference: PMID:41676145
    reference_title: Expanding the clinical and immunological phenotypes of COPB1 deficiency.
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunological characteristics include severe CD4+ lymphopenia, poor specific antibody responses, and impaired T-cell proliferation"
    explanation: States the CD4+ lymphopenia reported in the COPG1 patients.

- category: Laboratory
  name: Impaired specific antibody response
  description: >-
    Poor antibody responses to specific antigens despite the presence of B
    cells, matching the poor antibody response of the knock-in mouse.
  phenotype_term:
    preferred_term: Poor specific antibody responses
    term:
      id: HP:0012475
      label: Impaired specific antibody response
  evidence:
  - reference: PMID:41676145
    reference_title: Expanding the clinical and immunological phenotypes of COPB1 deficiency.
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunological characteristics include severe CD4+ lymphopenia, poor specific antibody responses, and impaired T-cell proliferation"
    explanation: States the impaired specific antibody responses reported in the COPG1 patients.

- category: Laboratory
  name: Abnormal T cell proliferation
  description: >-
    Impaired T cell proliferation on stimulation. The binding is to the
    direction-neutral term because the available source says impaired without
    naming the stimulus, and the stimulus-specific HPO terms would assert more
    than the source does.
  phenotype_term:
    preferred_term: Impaired T-cell proliferation
    term:
      id: HP:0031379
      label: Abnormal T cell proliferation
  evidence:
  - reference: PMID:41676145
    reference_title: Expanding the clinical and immunological phenotypes of COPB1 deficiency.
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunological characteristics include severe CD4+ lymphopenia, poor specific antibody responses, and impaired T-cell proliferation"
    explanation: States the impaired T cell proliferation reported in the COPG1 patients.

genetic:
- name: COPG1
  gene_term:
    preferred_term: COPG1
    term:
      id: hgnc:2236
      label: COPG1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  presence: PRESENT
  frequency: the only gene reported for this disorder
  notes: >-
    COPG1 encodes the gamma-1 subunit of the COPI coatomer. One homozygous
    missense allele, p.K652E, is reported, in five siblings of a single
    consanguineous kindred. There is no second family and no second allele, so
    the gene-disease relationship rests on one sibship plus a knock-in mouse
    carrying the same substitution.
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:33529166
    reference_title: "Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "homozygous p.K652E mutation in the γ1 subunit of COPI (γ1-COP)"
    explanation: Identifies COPG1 (gamma-1 COP) as the mutated gene in the affected siblings.
  - reference: PMID:41676145
    reference_title: Expanding the clinical and immunological phenotypes of COPB1 deficiency.
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in COPG1 have been reported as a cause of combined immunodeficiency"
    explanation: >-
      Independent restatement that COPG1 causes combined immunodeficiency.
      Quoted from the introduction of a COPB1 report rather than from its own
      results.

prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    Five affected siblings from one consanguineous Omani kindred are the only
    reported patients found during curation. No prevalence, incidence or
    carrier-frequency estimate exists, and Orphanet records no epidemiology for
    ORPHA:718017, so no rate is given here.
  evidence:
  - reference: PMID:33529166
    reference_title: "Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Five siblings with persistent bacterial and viral infections"
    explanation: The reported case count on which this record rests.

diagnosis:
- name: Molecular genetic testing for biallelic COPG1 variants
  description: >-
    There is no functional screening assay in clinical use. The diagnosis is
    made by finding a biallelic COPG1 variant in a child with combined
    immunodeficiency, CD4+ lymphopenia and poor specific antibody responses.
    Because the disorder is known from a single kindred, a novel COPG1 variant
    found in another family will need functional support, for which the
    published assay is loss of coatomer binding to the KDEL receptor with
    failure of chaperone retrieval.
  evidence:
  - reference: PMID:33529166
    reference_title: "Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The mutation disrupts COPI binding to the KDEL receptor and impairs the retrieval of KDEL-bearing chaperones from the Golgi to the ER."
    explanation: >-
      Supports the functional-confirmation part of this diagnostic approach
      only: it names the assays that established pathogenicity of the reported
      allele, and says nothing about the sequencing step that finds a variant.

differential_diagnoses:
- name: COPA syndrome
  description: >-
    The other coatopathy of retrograde Golgi-to-ER transport, and the one a
    COPG1 patient is most likely to be tested for. COPA syndrome is
    autosomal dominant and is an interferonopathy driven by cGAS/STING
    activation, presenting with lung haemorrhage and arthritis rather than with
    a combined immunodeficiency.
  distinguishing_features:
  - COPA syndrome is dominantly inherited; IMD128 is recessive.
  - COPA syndrome presents as autoinflammation and interstitial lung disease rather than as infection susceptibility.
  evidence:
  - reference: PMID:35484149
    reference_title: Deficiency in coatomer complex I causes aberrant activation of STING signalling.
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "The disease is caused by autosomal dominant mutations in the COPA gene"
    explanation: >-
      Sources the inheritance half of the distinction. Quoted from the
      introduction, where it restates the established mode of inheritance of
      COPA syndrome.
  - reference: PMID:35484149
    reference_title: Deficiency in coatomer complex I causes aberrant activation of STING signalling.
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "including interstitial lung disease with or without pulmonary haemorrhage, inflammatory arthritis, immune-mediated kidney disease and autoantibodies"
    explanation: >-
      Sources the presentation half of the distinction: COPA syndrome presents
      with inflammatory organ disease rather than with infection
      susceptibility. Quoted from the introduction.
  - reference: PMID:35484149
    reference_title: Deficiency in coatomer complex I causes aberrant activation of STING signalling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Genetic deletion of COPI subunits COPG1 or COPD similarly induces type I IFN activation in vitro, which suggests that inflammatory diseases associated with mutations in other COPI subunit genes may exist."
    explanation: >-
      Establishes that the two disorders share a retrograde-transport lesion
      and that the interferon arm is not unique to COPA, which is why the
      differential turns on inheritance and presentation rather than on
      pathway.

- name: COPB1 deficiency
  description: >-
    The beta subunit counterpart. COPB1 deficiency also produces a combined
    immunodeficiency through the same coatomer, alongside neurological
    features, so it is a genotype-level rather than a phenotype-level
    distinction.
  distinguishing_features:
  - COPB1 deficiency carries neurological manifestations not reported in the COPG1 kindred.
  evidence:
  - reference: PMID:41676145
    reference_title: Expanding the clinical and immunological phenotypes of COPB1 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This report documents a rare combined immunodeficiency disorder with neurological manifestations"
    explanation: Establishes COPB1 deficiency as a combined immunodeficiency with neurological features.

animal_models:
- name: Copg1 K652E knock-in mouse
  species: Mouse
  genotype: Copg1 K652E homozygous knock-in
  description: >-
    A mouse carrying the patients' substitution. Under specific-pathogen-free
    conditions it shows the cellular lesion (ER stress in activated
    lymphocytes, poor antibody responses, activation-induced T cell apoptosis)
    but normal T cell numbers and proliferation; the patients' proliferation
    defect and lymphopenia appear only after the animals are exposed to the
    microbial burden of pet store mice.
  publication: PMID:33529166
  genes:
  - preferred_term: COPG1
    term:
      id: hgnc:2236
      label: COPG1
  modeled_mechanisms:
  - target: Endoplasmic Reticulum Stress in Activated Lymphocytes
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: >-
      The knock-in carries the patients' exact substitution and reproduces the
      ER stress in activated T and B cells.
    readouts:
    - name: ER stress in activated T and B cells
      target: Endoplasmic Reticulum Stress in Activated Lymphocytes
      direction: INCREASED
      interpretation: The cellular lesion the human allele is proposed to cause.
      evidence:
      - reference: PMID:33529166
        reference_title: "Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Homozygous Copg1K652E mice had increased ER stress in activated T and B cells"
        explanation: Reports the measured increase in ER stress in activated lymphocytes.
    evidence:
    - reference: PMID:33529166
      reference_title: "Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Homozygous Copg1K652E mice had increased ER stress in activated T and B cells"
      explanation: Supports treating this knock-in as informative for the ER stress node.
  - target: Increased Apoptosis of Activated T Cells
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: >-
      T cells are present in normal numbers and proliferate normally but die on
      activation.
    readouts:
    - name: Apoptosis of T cells upon activation
      target: Increased Apoptosis of Activated T Cells
      direction: INCREASED
      interpretation: Establishes that the defect is conditional on activation rather than developmental.
      evidence:
      - reference: PMID:33529166
        reference_title: "Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "normal numbers of T cells that proliferated normally, but underwent increased apoptosis upon activation"
        explanation: Reports the activation-induced apoptosis measurement.
  - target: Defective Humoral and Cellular Immunity
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      The organism-level phenotype appears only under microbial exposure: after
      cohousing with pet store mice the mutants lost weight and developed
      lymphopenia and defective T cell proliferation resembling the patients.
    limitations: >-
      Under specific-pathogen-free housing the mutant mice have normal T cell
      numbers and normal proliferation, so the model reproduces the patients'
      systemic immune failure only when the environmental antigen burden is
      raised. The patients' persistent CMV and EBV viremia has no counterpart
      in the model at all, since neither virus infects mice.
    readouts:
    - name: Weight, lymphocyte count and T cell proliferation after pet store mouse exposure
      target: Defective Humoral and Cellular Immunity
      direction: DECREASED
      interpretation: The systemic phenotype that the authors state recapitulates the patients' findings.
      evidence:
      - reference: PMID:33529166
        reference_title: "Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Exposure of the mutants to pet store mice caused weight loss, lymphopenia, and defective T cell proliferation that recapitulated the findings in the patients."
        explanation: Reports the measured systemic phenotype and its dependence on microbial exposure.
  evidence:
  - reference: PMID:33529166
    reference_title: "Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Homozygous Copg1K652E mice had increased ER stress in activated T and B cells"
    explanation: Identifies the genotype of the knock-in model and the lesion it carries.

experimental_models:
- name: CRISPR/Cas9 COPG1-deficient HeLa and THP-1 cell lines
  description: >-
    Complete deletion of COPG1 in human cell lines, used to ask whether the
    retrograde-transport lesion of COPA syndrome generalises across COPI
    subunits. It does: COPG1-null cells show the same shift of KDEL-tagged
    chaperones towards the Golgi, and they activate cGAS/STING and type I
    interferon signalling spontaneously.
  experimental_model_type: CELL_LINE
  publication: PMID:35484149
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  modeled_mechanisms:
  - target: Impaired Retrieval of KDEL-Bearing Chaperones to the ER
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Deleting COPG1 reproduces the retrograde-trafficking defect, measured as
      KDEL signal redistributing onto the cis-Golgi.
    limitations: >-
      This is a complete null, not the patients' missense allele, and it is a
      HeLa or THP-1 cell rather than a lymphocyte. The patients' substitution
      leaves the subunit expressed and incorporated into the coat and disables
      one interaction, so a deletion may overstate the functional loss and may
      engage consequences the missense allele does not.
    evidence:
    - reference: PMID:35484149
      reference_title: Deficiency in coatomer complex I causes aberrant activation of STING signalling.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "These results indicate that genetic deletion of COPA, COPG1 or COPD results in impaired retrograde trafficking"
      explanation: Reports the retrograde-trafficking defect measured in COPG1-deleted cells.
  evidence:
  - reference: PMID:35484149
    reference_title: Deficiency in coatomer complex I causes aberrant activation of STING signalling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "only deletion of COPG1 resulted in spontaneous phosphorylation of STAT1 and inflammatory gene transcription"
    explanation: >-
      Reports that COPG1 loss, unlike COPG2 loss, drives spontaneous
      inflammatory signalling, which is the finding that makes this model
      relevant beyond the trafficking defect.

treatments:
- name: Tauroursodeoxycholic acid (preclinical only)
  description: >-
    The ER stress-relieving bile acid corrected the immune defects of the
    knock-in mice and reversed the phenotype the mutants acquired after pet
    store mouse exposure. This is a mouse result. No patient has been reported
    to receive it for this disorder, no dose or schedule is established, and it
    is recorded here because it identifies the mechanistic node that is
    druggable, not because it is a recommended therapy.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tauroursodeoxycholic acid
      term:
        id: CHEBI:80774
        label: tauroursodeoxycholic acid
  target_mechanisms:
  - target: Endoplasmic Reticulum Stress in Activated Lymphocytes
    description: >-
      The agent acts on the ER stress node rather than on the trafficking
      defect upstream of it, which is why correction is possible without
      restoring chaperone retrieval.
    evidence:
    - reference: PMID:33529166
      reference_title: "Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The ER stress-relieving agent tauroursodeoxycholic acid corrected the immune defects of the mutants"
      explanation: Reports correction of the immune defect by an agent acting on ER stress.
  evidence:
  - reference: PMID:33529166
    reference_title: "Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "tauroursodeoxycholic acid corrected the immune defects of the mutants and reversed the phenotype they acquired following exposure to pet store mice"
    explanation: The only therapeutic result reported for this disorder, and it is in the mouse.

discussions:
- discussion_id: copg1_human_treatment_absent
  kind: KNOWLEDGE_GAP
  prompt: >-
    What is the standard of care for a child with COPG1 deficiency, and does
    immunoglobulin replacement, antimicrobial prophylaxis or haematopoietic
    stem cell transplantation change outcome?
  attaches_to:
  - treatments#
  rationale: >-
    No management recommendation could be sourced for this disorder during
    curation. The only reported therapeutic result is correction of the mouse
    phenotype by tauroursodeoxycholic acid. Because the mechanism is a
    cell-intrinsic trafficking defect present in every cell, whether a
    haematopoietic graft would be curative is not obvious and has not been
    reported.

- discussion_id: copg1_type_i_interferon_in_patients
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does the cGAS/STING-driven type I interferon activation seen in
    COPG1-deleted cell lines occur in patients carrying the p.K652E missense
    allele, and if so does it contribute to their disease?
  attaches_to:
  - pathophysiology#Impaired Retrieval of KDEL-Bearing Chaperones to the ER
  rationale: >-
    Complete deletion of COPG1 in HeLa and THP-1 cells activates STING and type
    I interferon signalling, and the authors explicitly raise the possibility of
    inflammatory disease from other COPI subunit genes. The reported COPG1
    patients are described as infection-prone rather than autoinflammatory, and
    a missense allele that leaves the subunit in the coat is not the same lesion
    as a null. No interferon signature has been reported in these patients.

- discussion_id: copg1_mouse_needs_microbial_exposure
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Why does the Copg1 K652E mouse reproduce the patients' lymphopenia and T
    cell proliferation defect only after exposure to pet store mice, and what
    does that imply for the human disease?
  attaches_to:
  - animal_models#Mouse
  - pathophysiology#Defective Humoral and Cellular Immunity
  rationale: >-
    Under specific-pathogen-free housing the knock-in mouse has normal T cell
    numbers and normal proliferation, and only acquires the patients' systemic
    findings once cohoused with pet store mice. The cellular lesion is
    therefore faithful while the organism-level phenotype is conditional on
    antigenic burden. If that dependence holds in humans, it would predict that
    severity tracks cumulative infection exposure rather than genotype alone,
    which bears directly on whether early prophylaxis is worthwhile. It is
    untested.

references:
- reference: PMID:33529166
  title: "Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex."
- reference: PMID:41676145
  title: Expanding the clinical and immunological phenotypes of COPB1 deficiency.
- reference: PMID:35484149
  title: Deficiency in coatomer complex I causes aberrant activation of STING signalling.
- reference: ORPHA:718017
  title: Combined immunodeficiency due to COPG1 deficiency

notes: >-
  Identity. The stub for MONDO:0975834 carried no gene, so the identity was
  established from the term's own cross-references rather than from memory.
  MONDO:0975834 is an exact match to OMIM:620983 (IMMUNODEFICIENCY 128), and
  Orphanet's record for the same OMIM entry, ORPHA:718017, names it "Combined
  immunodeficiency due to COPG1 deficiency". The gene assignment therefore
  rests on the MONDO-OMIM-Orphanet chain plus the primary report, PMID:33529166,
  which describes the five-sibling Omani kindred homozygous for COPG1 p.K652E.
  No second family and no second allele were found in a PubMed search of COPG1
  in title and abstract.

  MONDO status. MONDO has scheduled MONDO:0975834 for obsoletion and merger
  into MONDO:0800136, on the stated grounds that the two terms denote the same
  concept. The term was still live and not flagged obsolete when this entry was
  written, so it remains the primary disease_term and the successor is recorded
  as an exact match in mappings. The stub did not carry the obsoletion-candidate
  flag, which is worth knowing when reading the stub queue for other terms.

  Lump or split. This is curated as its own Disease entry rather than as a
  has_subtypes entry on a neighbour. The knowledge base holds no COPG1 entry and
  no coatopathy entry of any kind, so there is no parent disease for it to sit
  under, and the numbered immunodeficiencies in kb/disorders are each their own
  entry. The pathograph is a single conserved chain from one allele to one
  clinical picture, which is what a Disease entry asks for. It is a candidate
  member of the Combined_Immunodeficiencies_IEIs grouping; that grouping was not
  edited here.

  Gaps, and why they are gaps rather than omissions. There is no prevalence,
  incidence or carrier-frequency figure anywhere, and Orphanet records no
  epidemiology for ORPHA:718017. There is no GeneReviews chapter. There is no
  clinical trial and no reported human treatment: the only therapeutic result is
  in the knock-in mouse. The primary report is not available as full text
  through the reference cache used here, only as its abstract, so several
  clinical details that the paper does report - the specific organisms cultured,
  bronchiectasis in three of the siblings, the death of one sibling at 3.5
  years, immunoglobulin replacement - are deliberately absent from this entry
  rather than asserted from a source that cannot be quoted. The patient-level
  clinical and immunological features that are present here are quoted from the
  introduction of PMID:41676145, a report on the related COPB1 disorder that
  restates the published COPG1 findings; those items carry quote_role BACKGROUND
  for that reason. An entry built from the full text of PMID:33529166 would be
  substantially richer and remains the obvious next pass.

  Variant grading. genetic_context on the COPG1 node records zygosity, origin
  and allele type but not functional_impact_category. The quotable source says
  the substitution disrupts COPI binding to the KDEL receptor; whether that is
  best graded a partial or an interaction-selective loss of function depends on
  what the mutant coat still does, which is reported in the paper's full text
  rather than its abstract. The field is left empty rather than graded from an
  inference.

  Ontology bindings. HP:0002783 Recurrent lower respiratory tract infections is
  used where the source says "recurrent pulmonary infections": pulmonary names
  the lung, which is the lower respiratory tract, so the term asserts no more
  than the source does. HP:0031379
  Abnormal T cell proliferation is used rather than one of the stimulus-specific
  children (HP:0031381 mitogen-induced, HP:0031382 anti-CD3/28-induced) because
  the quotable source says only "impaired T-cell proliferation". Orphanet's
  record maps ORPHA:718017 to ICD-10 D81.8 as a narrower-than relation; no
  icd10cm mapping is recorded here because that binding could not be resolved
  against an ontology source during curation.
📚

References & Deep Research

References

4
PMID:33529166
Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex.
No top-level findings curated for this source.
PMID:41676145
Expanding the clinical and immunological phenotypes of COPB1 deficiency.
No top-level findings curated for this source.
PMID:35484149
Deficiency in coatomer complex I causes aberrant activation of STING signalling.
No top-level findings curated for this source.
ORPHA:718017
Combined immunodeficiency due to COPG1 deficiency
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Immunodeficiency_128 · 2026-09-24T17:08:45Z · View source

De novo curation of immunodeficiency 128 (MONDO:0975834, OMIM:620983, ORPHA:718017). The stub named no gene; identity was established from the MONDO term's own cross-references (exact match to OMIM:620983, whose Orphanet counterpart ORPHA:718017 is titled 'Combined immunodeficiency due to COPG1 deficiency') and then from the primary report, PMID:33529166 (Bainter et al., J Clin Invest 2021), describing five siblings of a consanguineous Omani kindred homozygous for COPG1 p.K652E. A PubMed title/abstract search for COPG1 found no second family and no second allele. Curated as its own Disease entry: the knowledge base holds no COPG1 or coatomer entry for it to be a subtype of, and the pathograph is a single conserved chain. MONDO has scheduled MONDO:0975834 for merger into MONDO:0800136; the term was still live at curation, so it remains the primary disease_term and the successor is recorded as a skos:exactMatch mapping. Deep research: falcon was requested and returned HTTP 402 (out of credits), so the claude_code fallback produced research/Immunodeficiency_128-deep-research-claude_code.md; just preflight-dr returned SKIP (MONDO records no causal gene for the term, so the gene-identity check cannot discriminate) and the report's dominant gene, COPG1, agrees with the independently established identity. The report carries needs_review: true for one unsupported quote and one mislabelled placeholder HPO term, neither of which was used. The entry is deliberately thin. The primary report is available to the reference cache only as its abstract, so clinical details it reports in full text (organisms cultured, bronchiectasis in three siblings, one death at 3.5 years, immunoglobulin replacement) are absent rather than asserted; patient-level clinical and immunological features come instead from the introduction of PMID:41676145, carrying quote_role BACKGROUND. No prevalence figure, no GeneReviews chapter, no clinical trial and no human treatment could be sourced; the only therapeutic result is tauroursodeoxycholic acid rescue in the knock-in mouse. Validated with just validate, validate-terms, check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms, check-enum-values, check-snippet-length, check-title-snippets, check-snippet-grading, check-folded-hyphens, check-environmental-evidence, check-coarse-phenotypes, check-genereviews --online, list-gene-term-mismatches, pytest tests/test_data.py and validate-disorders, the snippet gates under linkml-reference-validator 0.3.0rc1.

Claude Code ▸
Immunodeficiency 128 (IMD128) — Comprehensive Research Report
claude-haiku-4-5-20251001, claude-sonnet-5 10 citations 2026-09-24T17:04:05.313266

Immunodeficiency 128 (IMD128) — Comprehensive Research Report

1. Disease Information

Overview. Immunodeficiency-128 (IMD128) is an autosomal recessive combined immunodeficiency (CID) caused by a homozygous missense mutation in COPG1, which encodes the γ1 subunit of the coat protein complex I (COPI). COPI mediates retrograde vesicular trafficking of cargo — including KDEL-motif-bearing endoplasmic reticulum (ER) chaperones — from the Golgi back to the ER. The single reported kindred (five siblings of consanguineous Omani parents) presented in the first year of life with recurrent bacterial and viral infections, failure to thrive, hepatitis, and progressive bronchiectasis, with a combined (T- and B-cell) immunodeficiency phenotype. The molecular mechanism established by the discovery study is that loss of γ1-COP–mediated KDEL-receptor engagement impairs retrieval of chaperones (BiP/GRP78, calreticulin, protein disulfide isomerase) to the ER, producing exaggerated, activation-induced ER stress and unfolded protein response (UPR) signaling selectively in lymphocytes — explaining the immune-restricted phenotype despite COPI's ubiquitous cellular role (Bainter et al., 2021, PMID:33529166).

Key identifiers: - OMIM phenotype: #620983 — IMMUNODEFICIENCY 128; IMD128 (https://omim.org/entry/620983) - OMIM gene: 615525 — COATOMER PROTEIN COMPLEX, SUBUNIT GAMMA-1; COPG1 - Gene symbol / HGNC: COPG1, HGNC:2236 - Cytogenetic location: 3q21.3 - MONDO: MONDO:0975834 (as supplied by the curation stub — not independently cross-verified against a MONDO release in this session; verify with runoak before binding) - Inheritance: Autosomal recessive - Primary literature source: Bainter W, et al. "Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex." J Clin Invest.* 2021. PMID:33529166 (https://www.jci.org/articles/view/140494)

Synonyms/alternative names: COPG1 deficiency; γ1-COP deficiency; combined immunodeficiency due to COPG1 mutation. No ICD-10/ICD-11 code specific to this ultra-rare monogenic entity was found (it would fall under the broad "Combined immunodeficiency, unspecified" / D81 family in ICD-10). No dedicated MeSH heading exists; it is indexed under "Severe Combined Immunodeficiency" and "COPI Vesicle Coat"-adjacent terms in PubMed.

Data provenance: All disease-level information here derives from a single aggregated disease-mechanism study (whole-exome sequencing of an index family plus mechanistic mouse/cell-line follow-up) rather than an EHR-based cohort or registry — this is a gene-discovery paper, not population-level disease surveillance. There is no OMIM Clinical Synopsis text retrievable in this session (OMIM blocked direct fetch with HTTP 403); the clinical/laboratory detail below is drawn from the JCI primary article and searches, not the OMIM Clinical Synopsis itself — this is a gap to independently verify against OMIM's full entry before curation (flagging per the attribution rule: I did not access omim.org directly).

2. Etiology

Disease Causal Factor: Purely genetic/monogenic. Homozygosity for the COPG1 missense variant c.1954A>G (p.Lys652Glu, p.K652E) is the sole reported cause. No environmental, infectious, or multifactorial contribution to disease initiation is described; the clinical phenotype's severity, however, is modulated by environmental microbial exposure (see Mechanism section — mouse cohousing data).

Genetic risk factors: - The single causal variant identified to date is homozygous COPG1 p.K652E (Bainter et al. 2021, PMID:33529166), found in 5 affected siblings, heterozygous (carrier, unaffected) in both parents — consistent with autosomal recessive inheritance. - Consanguinity is the dominant identified genetic/demographic risk factor: the parents were first-degree or close relatives from Oman, and consanguinity is the mechanism by which a rare recessive allele became homozygous in multiple siblings. - No modifier genes, no digenic contribution, and no other COPG1 alleles have been reported in the literature to date — this remains a single-family, single-variant disease as of this search (September 2026). - I was unable to retrieve COPG1-specific gnomAD constraint metrics (pLI / LOEUF / missense Z) in this session; this should be pulled directly from the gnomAD browser before curation rather than assumed. COPG1 is broadly expressed and essential (it is the major γ-COP paralog used in most tissues, versus the minor paralog γ2-COP/COPG2), so a priori it is plausible the gene is constrained against loss-of-function, but I have no sourced number to cite.

Environmental risk factors: None reported as causal. However, environmental microbial exposure is a documented disease-severity modifier (not a cause): in the Copg1^K652E mouse model, animals raised under specific-pathogen-free (SPF) conditions had a comparatively mild baseline phenotype (hypogammaglobulinemia, defective antibody responses, but grossly normal lymphocyte numbers/proliferation), whereas cohousing with pet-store mice (i.e., exposure to a naturalistic, diverse microbial burden) for 22 days precipitated overt disease: progressive weight loss to ~70% of baseline, T-cell lymphopenia, severely impaired T-cell proliferation, hypergammaglobulinemia, and elevated serum TNF-α, IFN-γ, and IL-6 (Bainter et al. 2021, PMID:33529166). This is strong evidence for a gene-by-environment interaction: the COPG1 mutation creates increased susceptibility to ER stress under the high secretory demand imposed by real-world pathogen exposure, and a low-antigen-burden environment can mask or attenuate the phenotype.

Protective factors: None identified in the human literature. In the mouse model, the chemical chaperone tauroursodeoxycholic acid (TUDCA) — a bile-acid-derived ER-stress-relieving agent — substantially reversed multiple phenotypic and molecular defects both in vitro and in vivo (see Treatment, below); this is best framed as a pharmacologic/therapeutic rescue rather than a naturally occurring protective factor, but it is directly relevant to the disease's gene-environment mechanism (buffering ER stress reduces phenotype severity).

Gene-environment interaction: As above — the core mechanistic insight of the primary paper is precisely a G×E interaction: γ1-COP loss of function creates latent ER-stress vulnerability that is unmasked specifically by the high secretory/proliferative demand lymphocytes experience upon antigenic/microbial activation. This is the central causal-chain logic for the mechanism section below.

3. Phenotypes

All phenotypes below are drawn from the 5-patient Omani sibling cohort in Bainter et al. 2021 (PMID:33529166); frequencies are reported as fractions of 5 unless stated otherwise. Suggested HPO terms are provided for KB curation; these are leads and must be verified against the HPO ontology before binding.

Phenotype Type Onset/Frequency Suggested HPO term
Recurrent bacterial respiratory infections (H. influenzae, S. pneumoniae, Moraxella) Symptom/clinical sign Onset in first year of life; all 5 patients HP:0002090 Bronchopneumonia / HP:0011947 Recurrent bronchopulmonary infections
Bronchiectasis Physical/imaging finding Chronic; 3/5 patients HP:0002110 Bronchiectasis
Chronic/persistent CMV viremia Laboratory abnormality Persistent; all 5 patients HP:0033132 (or free-text — no dedicated "CMV viremia" HPO term is standard; consider HP:0002718 Recurrent infections plus a qualifiers/notes annotation naming the pathogen)
Chronic EBV viremia Laboratory abnormality Persistent; 2/5 patients see above
Parvovirus B19 viremia Laboratory abnormality 1/5 patients see above
Failure to thrive (weight/height <3rd percentile) Physical/growth Chronic, early-onset HP:0001508 Failure to thrive
Hepatitis Clinical sign Present in all 5 patients HP:0012115 Chronic hepatitis (or HP:0002240 Hepatomegaly if hepatomegaly specifically documented — verify from full text)
Death from respiratory failure/multiorgan dysfunction Outcome Patient 4, age 3.5 years HP:0002205 Recurrent respiratory infections as contributor; mortality is an outcome field, not an HPO phenotype
CD4+ T-cell lymphopenia Laboratory abnormality Severe; all 5 patients (with one patient reported normal at birth, declining later) HP:0005403 CD4-positive T-cell lymphopenia
Variable/modest CD8+ T-cell lymphopenia Laboratory abnormality Variable; present in a subset HP:0032179 (verify exact CD8 lymphopenia term)
Decreased NK cells Laboratory abnormality Variable HP:0040218 Decreased NK cell number (verify)
Poor T-cell proliferation to PHA/anti-CD3 Laboratory/functional Present HP:0032234 Impaired T cell proliferation (verify)
Impaired antibody production / poor vaccine response (tetanus, diphtheria, HBV, measles) Laboratory/functional Poor booster response (<4-fold titer rise); absent HBV and measles responses HP:0002846 Abnormal T cell physiology / HP:0002846-adjacent; more precisely HP:0031409 Abnormal antibody level or a vaccine-response-specific term — verify
Diminished in-vitro IgG secretion (B cells stimulated with anti-CD40+IL-4) Laboratory/functional (ex vivo assay) Present Not a clinical HPO phenotype per se — functional assay finding, appropriate for biochemical/functional description rather than phenotypes
Elevated or normal serum IgG; normal/near-normal IgA, IgM Laboratory Variable HP:0002850 Decreased circulating IgG level does NOT apply uniformly (IgG was normal/elevated) — do not over-assert

Severity/progression: Onset is uniformly in the first year of life (congenital/infantile-onset CID). The course is progressive in at least one patient (fatal at 3.5 years) and chronic/persistent in survivors (chronic viremia, progressive bronchiectasis). Severity appears to fluctuate with microbial/antigenic exposure burden, consistent with the mouse-model G×E data above — this is an inference from the animal model, not directly demonstrated longitudinally in the human patients within the source material I retrieved.

Quality of life impact: Not formally studied (no PROMIS/EQ-5D/SF-36 data found); QoL impact can be reasonably inferred as substantial given chronic infection burden, growth failure, and one death, but this is inference, not sourced measurement — flag as such in any KB notes:.

4. Genetic/Molecular Information

Causal gene: COPG1 (HGNC:2236; OMIM *615525; chromosome 3q21.3). Encodes the γ1 subunit of the heptameric coatomer (COPI) complex (subunits α/COPA, β/COPB1, β′/COPB2, γ/COPG1, δ/ARCN1, ε/COPE, ζ/COPZ1), which coats vesicles budding from the Golgi for retrograde transport to the ER.

Pathogenic variant: - Variant: c.1954A>G; p.Lys652Glu (p.K652E) (NM_016128 reference transcript implied by standard nomenclature; exact transcript ID not independently confirmed in this session — verify before curation) - Zygosity: Homozygous in all 5 affected siblings; heterozygous (carrier, clinically unaffected) in both parents - Variant type: Missense - Classification: Not independently retrieved from ClinVar in this session — should be checked via ClinVar/VarSome before curation (the variant is very likely listed given the JCI publication, but I have not confirmed the classification string) - Population frequency: Not found in the search results retrieved (gnomAD-specific allele frequency for this exact variant was not confirmed in this session — should be checked directly) - Origin: Germline - Functional consequence: Loss-of-function at the level of a specific protein-protein interaction (structural/interaction-selective LOF) rather than global loss of γ1-COP protein or complete abrogation of all COPI function. Structural modeling in the primary paper predicts the mutation disrupts two stabilizing bonds in the appendage domain of γ1-COP: "a salt bridge between K652 and the carboxyl side chain of E757 and a hydrogen bond between K652 and the main chain carbonyl oxygen of D762" (Bainter et al. 2021, PMID:33529166). Functionally, the mutant coatomer retains normal binding to classic dilysine-motif cargo (e.g., Wbp1) but loses direct binding to the KDEL receptor (KDELR) cytoplasmic tail — i.e., a selective, cargo-specific trafficking defect, not a general COPI assembly failure.

Modifier genes: None established. The paper does note that the paralogous subunit γ2-COP (encoded by COPG2) does not compensate for γ1-COP loss in lymphoid tissue, which may explain the immune-restricted phenotype despite COPI's role in all cells — γ2-COP may substitute sufficiently in non-lymphoid tissues, a mechanistic hypothesis rather than a formally proven modifier relationship.

Epigenetic information: None reported; not applicable/not studied for this disorder.

Chromosomal abnormalities: None — this is a single-nucleotide missense substitution, not a structural/copy-number variant.

Suggested gene binding for KB: gene_term → hgnc:2236 (COPG1); functional_impact_category on the genetic_context block should likely be a selective/partial loss-of-function category (e.g., PARTIAL_LOSS_OF_FUNCTION) rather than a full LOSS_OF_FUNCTION, given the interaction-selective mechanism — this is a curatorial judgment call to make against the primary paper's own framing, not something I am asserting definitively here.

5. Environmental Information

Environmental factors: Not causal for disease initiation (monogenic recessive disease). The key environmental factor is microbial/antigenic exposure burden as a disease-severity modifier, demonstrated experimentally in the mouse model via cohousing with pet-store mice (a standard model for simulating "wild"/naturalistic microbial exposure) versus SPF housing (Bainter et al. 2021, PMID:33529166). No human environmental epidemiology (toxin, occupational, pollution) is relevant or reported.

Lifestyle factors: Not applicable — this is an early-onset monogenic pediatric CID; no lifestyle/behavioral contribution is described.

Infectious agents: Infection is a consequence/manifestation of the immunodeficiency rather than a cause of the disease itself, but specific pathogens recur prominently and are clinically important for the disease's natural history: - Bacterial: Haemophilus influenzae, Streptococcus pneumoniae, Moraxella species (recurrent respiratory infections/pneumonia) - Viral (chronic/persistent viremia, reflecting impaired antiviral clearance): cytomegalovirus (CMV, all 5 patients), Epstein-Barr virus (EBV, 2/5 patients), parvovirus B19 (1/5 patients)

For an environmental[] entry in a KB curation, these would likely be modeled with environmental_effect: EXACERBATES or as downstream infection phenotypes rather than as TRIGGERS of the underlying disease (the disease is present from birth/genetically; infections exacerbate/reveal the clinical course).

6. Mechanism / Pathophysiology

Causal chain (ordered, from the primary paper's mechanistic model)

  1. Homozygous COPG1 c.1954A>G (p.K652E) disrupts the appendage-domain structure of γ1-COP, abolishing two predicted stabilizing bonds (K652–E757 salt bridge; K652–D762 hydrogen bond). (Demonstrated: structural modeling + biochemical binding assays.)
  2. The structurally altered γ1-COP fails to bind the cytoplasmic KDEL-receptor (KDELR) tail, while retaining normal binding to classic dilysine-motif cargo such as Wbp1 — i.e., a cargo-selective defect in coatomer function rather than global COPI failure. (Demonstrated: direct binding assays.)
  3. Loss of coatomer–KDELR engagement impairs retrograde Golgi-to-ER retrieval of KDEL-bearing ER-resident chaperones — BiP/GRP78, calreticulin, protein disulfide isomerase (PDI) — leaving them mislocalized toward/at the Golgi instead of recycled to the ER. (Demonstrated: patient fibroblast VSVGts-KDELR/GM130 colocalization assay showing impaired retrograde transport.)
  4. Chronic chaperone mislocalization reduces the ER's folding/quality-control capacity, which is normally buffered at baseline but becomes rate-limiting under high secretory demand. (Inferred from downstream UPR activation data; not directly visualized as "folding failure" per se.)
  5. Upon lymphocyte activation (antigen receptor engagement, cytokine stimulation), the massive increase in secretory protein synthesis (immunoglobulin in B cells; cytokines in T cells) exceeds the ER's now-diminished folding capacity, precipitating pathological ER stress selectively in activated — but not resting — B and T cells. (Demonstrated: increased Xbp1/spliced Xbp1 (sXbp1), elevated BiP (Hspa5) expression, PERK-pathway activation with increased CHOP in activated mutant cells; reduced ER size in mutant B cells.)
  6. Sustained/exaggerated unfolded protein response (UPR) signaling in activated B cells impairs IgG secretion despite normal plasmablast differentiation and normal class-switch recombination — i.e., a post-differentiation secretory bottleneck rather than a defect in B-cell developmental commitment. (Demonstrated: normal CSR/plasmablast markers, but diminished IgG output.)
  7. In activated T cells, UPR/PERK-CHOP activation drives increased apoptosis and reduced cell viability, which secondarily reduces IFN-γ output (a viability effect, not an intrinsic cytokine-production defect) while proliferation and activation-marker expression remain broadly normal. (Demonstrated: apoptosis assays; proliferation and marker studies.)
  8. Clinically, impaired antigen-specific antibody production (from step 6) and impaired T-cell survival/effector persistence (from step 7) together produce a combined humoral and cellular immunodeficiency, manifesting as recurrent bacterial respiratory infections, chronic viremia (CMV/EBV/parvovirus B19), and poor vaccine responses. (Clinical observation in the index family, connected to the cellular mechanism by the paper's overall argument — this final clinical link is the paper's central inferential claim rather than a directly traced single-cell-to-bedside proof.)
  9. Branch — environmental modulation: Under low antigenic burden (SPF housing in mice), the residual UPR-buffering capacity is sufficient to keep the phenotype relatively mild (hypogammaglobulinemia, poor antibody response only); under high/naturalistic microbial exposure (pet-store cohousing), cumulative secretory/proliferative demand overwhelms buffering, producing overt lymphopenia, weight loss, and systemic inflammatory cytokine elevation (TNF-α, IFN-γ, IL-6) — showing the causal chain above is exposure-dependent in severity, not fixed. (Demonstrated directly in the mouse model.)
  10. Therapeutic rescue arm: Pharmacologic ER-stress relief with TUDCA (a chemical chaperone) normalizes sXbp1/Hspa5 expression, restores B-cell IgG secretion, corrects T-cell survival/IFN-γ output in vitro, and reverses antibody-response defects and the pet-store-exposure-induced phenotype in vivo — providing causal (not merely correlative) support for steps 4–8 by showing that relieving ER stress specifically reverses the downstream immune defects. (Demonstrated: in vitro and in vivo TUDCA rescue experiments.)

Category detail

  • Molecular pathways: COPI-mediated retrograde vesicular trafficking (Golgi→ER); KDEL-receptor cargo-retrieval pathway; IRE1–XBP1 and PERK–CHOP arms of the unfolded protein response (UPR). Suggested GO terms: GO:0006890 (retrograde vesicle-mediated transport, Golgi to ER); GO:0030968 (endoplasmic reticulum unfolded protein response); GO:0036498 (IRE1-mediated unfolded protein response); GO:0036499 (PERK-mediated unfolded protein response).
  • Cellular processes: Activation-induced apoptosis in T cells (GO:0006915 apoptotic process); impaired antibody secretion in B cells (GO:0002377 immunoglobulin production, or more specifically antibody secretion process — verify exact GO ID); ER stress response (GO:0034976 response to endoplasmic reticulum stress).
  • Protein dysfunction: γ1-COP loses a specific protein-protein interaction (KDELR binding) via disruption of two intramolecular stabilizing bonds in its appendage domain — a structurally localized, interaction-selective defect rather than global misfolding/instability of γ1-COP itself. Suggested UniProt entry: COPG1_HUMAN (UniProt Q9Y678).
  • Biochemical abnormalities: Defective KDEL-receptor engagement by coatomer; secondary chaperone (BiP/GRP78, calreticulin, PDI) mislocalization; secondary XBP1 splicing and CHOP induction as UPR markers.
  • Immune system involvement: Combined immunodeficiency — impaired humoral immunity (poor specific antibody responses despite normal B-cell numbers/differentiation) and impaired cellular immunity (CD4+ T-lymphopenia, reduced T-cell survival upon activation, poor T-cell proliferation to mitogen/anti-CD3). This is not autoimmunity/immune dysregulation (contrast with COPA syndrome, below) but a bona fide immunodeficiency.
  • Cell types/tissue involvement: Activated CD4+ and CD8+ T cells; activated (antigen/CD40+IL-4-stimulated) B cells and plasmablasts. Suggested CL terms: CL:0000624 (CD4-positive, alpha-beta T cell), CL:0000625 (CD8-positive, alpha-beta T cell), CL:0000236 (B cell), CL:0000980 (plasmablast).
  • Advanced/omics data: No transcriptomic, proteomic, single-cell, or spatial datasets were identified as publicly deposited for this specific disease in the sources retrieved; the primary paper's UPR-marker data (Xbp1/sXbp1, Hspa5, CHOP) were generated by targeted qPCR/immunoblot rather than genome-wide profiling, as best I can determine from the retrieved summary. Verify against the full JCI methods/supplement before asserting "no omics data exist."

Cross-paralog comparative mechanism (relevant differential/context)

Other COPI-subunit diseases illustrate that different subunits within the same heptameric complex can produce distinct immunophenotypes: - COPA syndrome (autosomal dominant, COPA, α-COP; OMIM #601924 gene) causes an immune dysregulation/autoinflammatory phenotype (interstitial lung disease ± pulmonary hemorrhage, inflammatory arthritis, immune-mediated kidney disease), mechanistically linked to aberrant STING pathway activation from COPI deficiency (Nature Communications 2022, PMID:35484149; Watkin et al., PMC6372856). - COPB1 deficiency (COPB1, β-COP) causes Baralle–Macken syndrome, combining neurodevelopmental features (global developmental delay, intellectual disability, early-onset cataracts) with combined immunodeficiency features (neutropenia, lymphopenia, impaired specific antibody responses) — a broader multisystem phenotype than IMD128 (PMID:41676145). - COPB2 loss-of-function variants cause a distinct skeletal/microcephaly phenotype, without the same immunodeficiency emphasis.

This positions IMD128/COPG1 deficiency as the coatomer-subunit disorder with the most immunologically "pure" combined-immunodeficiency phenotype identified to date, useful context for the KB's classifications (IUIS immunodeficiency category) and for distinguishing lump/split decisions from COPA syndrome and COPB1 deficiency, which should remain separate disease entries given their genetically and mechanistically distinct (dominant immune-dysregulation vs. recessive multisystem vs. recessive pure-CID) natures.

7. Anatomical Structures Affected

  • Organ level: Primary — respiratory system (recurrent pneumonia, bronchiectasis) and lymphoid/immune system (lymphopenia, impaired antibody production). Secondary — liver (hepatitis, present in all 5 patients), growth (failure to thrive, a systemic/endocrine-adjacent secondary effect). Suggested UBERON terms: UBERON:0001004 (respiratory system), UBERON:0002048 (lung), UBERON:0002107 (liver), UBERON:0002405 (immune system).
  • Tissue/cell level: Bronchial/pulmonary tissue (bronchiectasis); hepatic parenchyma; lymphoid tissue — specifically activated T and B lymphocytes as the mechanistically critical cell population (see Mechanism section for CL terms).
  • Subcellular level: Endoplasmic reticulum (chaperone retrieval failure, UPR activation; GO:0005783 endoplasmic reticulum) and Golgi apparatus (site of COPI vesicle budding and KDELR mislocalization; GO:0005794 Golgi apparatus). Suggested GO Cellular Component terms: GO:0030137 (COPI-coated vesicle), GO:0000139 (Golgi membrane).
  • Localization: No lateralization pattern reported (systemic/multi-organ, bilateral pulmonary disease implied by "bronchiectasis" without laterality specified).

8. Temporal Development

  • Onset: Infantile — recurrent infections beginning in the first year of life in all 5 reported patients. One patient (P5) had normal CD4+/CD8+ counts documented at birth, suggesting T-cell lymphopenia may develop postnatally/progressively rather than being present in utero — an important nuance for framing "onset."
  • Onset pattern: Insidious/chronic rather than acute, punctuated by recurrent infectious episodes.
  • Progression: Progressive and chronic. Bronchiectasis (an anatomically progressive, largely irreversible airway process) developed in 3/5 patients. One patient (P4) died at 3.5 years of age from respiratory failure and multiorgan dysfunction, indicating a potentially fatal, progressive course in at least a subset.
  • Disease course pattern: Chronic-persistent with recurrent infectious exacerbations (viremia is described as "persistent"/"chronic" rather than episodic-clearing).
  • Duration: Chronic, lifelong in survivors (no report of spontaneous resolution).
  • Remission: No spontaneous remission reported; TUDCA-based pharmacologic rescue in the mouse model is the only intervention shown to reverse (not merely stabilize) components of the phenotype, and this is preclinical, not yet a demonstrated human remission-inducing therapy.
  • Critical periods: Infancy/early childhood is the critical period for clinical presentation and, per the fatal case, mortality risk; no data on prenatal/neonatal screening windows.

9. Inheritance and Population

  • Epidemiology: IMD128 is described in exactly one kindred (5 affected siblings from one consanguineous Omani family) as of the primary 2021 publication — no formal prevalence or incidence estimate exists; it should be classified as ultra-rare / cases-in-literature only (n=5) for any Prevalence record (measure_type: CASES_IN_LITERATURE, prevalence_class: NOT_YET_DOCUMENTED or an ultra-rare qualitative tier if only "rare" language is used — do not fabricate a numeric rate).
  • Inheritance pattern: Autosomal recessive (confirmed — homozygous in affected siblings, heterozygous carrier parents).
  • Penetrance: Appears complete among the 5 homozygous siblings reported (all were symptomatic), though the sample size is too small to make a formal penetrance estimate, and possible variability is suggested by P5's normal birth T-cell counts versus later lymphopenia.
  • Expressivity: Variable — bronchiectasis in 3/5, chronic EBV viremia in 2/5, parvovirus B19 in only 1/5, and one death versus four survivors, indicating substantial variable expressivity even within one sibship carrying the identical genotype. This variability is consistent with — and mechanistically explained by — the gene-by-environment (microbial exposure) interaction demonstrated in the mouse model.
  • Genetic anticipation: Not applicable/not reported (not a repeat-expansion disorder).
  • Germline mosaicism: Not reported/not applicable (biallelic inheritance from two heterozygous carrier parents, not mosaicism).
  • Founder effect: Not established as a population founder variant; the variant was identified in one extended consanguineous family. Whether it represents an Omani/Arabian Peninsula founder allele versus a private familial variant is not determined from the sources retrieved.
  • Consanguinity role: Central — consanguinity is the mechanism by which the rare recessive allele reached homozygosity in this family; this is explicitly the demographic context of the discovery.
  • Carrier frequency: Not established/not found in population databases in this session.
  • Population demographics: Only Omani (Arabian Peninsula, Middle Eastern) ancestry is documented. No data on other populations, geographic distribution, sex ratio (the paper does not appear to specify sex distribution among the 5 siblings in the material retrieved — verify from full text), or age distribution beyond the pediatric-onset pattern described above.

10. Diagnostics

Laboratory tests (as performed in the index cohort): - Complete blood count with lymphocyte subset flow cytometry (CD4+, CD8+, B-cell, NK-cell enumeration) - T-cell proliferation assays (response to PHA and anti-CD3 stimulation) - Quantitative serum immunoglobulins (IgG, IgA, IgM) - Specific antibody titers to tetanus, diphtheria, hepatitis B, and measles (pre/post-booster) - In vitro B-cell functional assay: IgG secretion following anti-CD40 + IL-4 stimulation - Viral load monitoring (CMV, EBV, parvovirus B19 PCR/viremia) - Liver function tests (given universal hepatitis)

Genetic testing: - Whole-exome sequencing (WES) was the diagnostic modality that identified the causal COPG1 variant in this family — appropriate as first-tier testing in a suspected novel/undiagnosed CID, especially in a consanguineous pedigree where a homozygosity-mapping-informed WES approach is efficient. - No commercial single-gene or panel test specific to COPG1 CID was confirmed as available in this session (this is a very recently described, single-family gene-disease relationship; coverage on standard primary immunodeficiency gene panels should be checked directly against panel providers such as Invitae/GeneDx/Blueprint Genetics, and against Genomics England PanelApp, which does list COPG1 on its "Primary immunodeficiency or monogenic inflammatory bowel disease" panel per the search result above — https://panelapp.genomicsengland.co.uk/panels/398/gene/COPG1/). - Sanger sequencing was used to confirm the WES-identified variant and to test parental carrier status.

Genetic testing utility (general/inferred): For a CID presenting with the described phenotype, WES or WGS is likely to have higher diagnostic yield than a targeted panel given the extreme rarity/novelty of the gene-disease association; a comprehensive primary immunodeficiency gene panel that includes COPG1 would also be reasonable.

Clinical criteria: No standardized diagnostic criteria (e.g., ESID/PAGID criteria for CID) specific to IMD128 exist; diagnosis rests on the combination of clinical phenotype plus molecular confirmation of biallelic pathogenic COPG1 variants. Differential diagnosis should include other combined immunodeficiencies (SCID variants, other coatomer-subunit disorders such as COPB1 deficiency/Baralle–Macken syndrome, and other CIDs presenting with infantile recurrent infection, failure to thrive, and hepatitis) — distinguishing features from COPB1 deficiency include the presence of neurodevelopmental impairment and cataracts in the latter, which are not reported in IMD128.

Screening: No newborn screening protocol exists for this ultra-rare, recently described condition; it would not currently be detected by standard SCID newborn screening (TREC assay), since the reported patients had detectable (if reduced/declining) T-cell populations rather than a classic SCID-level absence of T cells — this is an inference based on the described lymphopenia pattern, not a directly stated TREC result.

11. Outcome/Prognosis

  • Survival/mortality: Of 5 reported patients, 1 (P4) died at age 3.5 years from respiratory failure and multiorgan dysfunction; the other 4 were alive at the time of publication (specific follow-up ages/duration not confirmed in the material retrieved in this session — verify from full text). This gives an observed case-fatality of 1/5 in the only reported cohort — far too small a sample for a formal survival-rate estimate, and this should be presented as raw case count, not extrapolated to a population rate.
  • Morbidity: Chronic bronchiectasis (3/5) represents a significant, largely irreversible morbidity affecting long-term pulmonary function. Chronic viremia (CMV/EBV/parvovirus B19) represents ongoing infectious morbidity. Hepatitis (5/5) represents chronic hepatic morbidity of unspecified severity/etiology attribution (viral vs. direct ER-stress-related hepatocyte injury is not distinguished in the sources retrieved).
  • Complications: Bronchiectasis, chronic viral infection/viremia, growth failure, and (in one case) fatal multiorgan dysfunction.
  • Quality of life: Not formally measured (see Section 3).
  • Prognostic factors: No formal prognostic model exists. Based on the mouse-model data, cumulative microbial/antigenic exposure burden is a plausible severity/prognostic modifier, and early recognition with reduced-exposure management (analogous to protective isolation in other CIDs) plus prompt antimicrobial and immunoglobulin support would be the biologically rational, though not yet clinically validated in humans, prognosis-modifying strategy.

12. Treatment

Established human clinical management: The primary source material retrieved does not specify the exact clinical management regimen used for the 5 index patients (e.g., whether IVIG replacement, prophylactic antimicrobials, or hematopoietic stem cell transplantation were used) — I could not confirm these details from the sources available in this session, and this should be verified directly from the JCI full text/supplement before curating specific treatments: entries with NCIT bindings. Given the phenotype (combined immunodeficiency with impaired antibody responses and recurrent bacterial/viral infection), standard-of-care management for CID would conventionally include: - Immunoglobulin replacement therapy (IVIG/SCIG) — NCIT term candidate: generic Pharmacotherapy (NCIT:C15986) with therapeutic_agent bound to an immunoglobulin product, if directly documented in the source - Antimicrobial prophylaxis - Consideration of hematopoietic stem cell transplantation (HSCT) as the only potentially curative option for a genetically defined CID

These are inferred, standard-of-care possibilities based on the disease category, not confirmed treatments documented for this specific cohort in the sources I retrieved — do not curate them into a KB entry as disease-specific evidence without independently sourcing the exact treatment history from the full JCI article or a follow-up case report.

Investigational/preclinical (mechanistically validated in the mouse model, not yet a clinical therapy): - Tauroursodeoxycholic acid (TUDCA) — an ER-stress-relieving chemical chaperone (a bile acid derivative). In the Copg1^K652E mouse model, TUDCA: - Normalized sXbp1 and Hspa5 mRNA expression to wild-type levels in mutant B cells in vitro - Restored IgG secretion in LPS+IL-4-stimulated mutant B cells in vitro - Corrected T-cell survival and IFN-γ secretion upon anti-CD3+anti-CD28 stimulation in vitro - Normalized IgG anti-TNP antibody responses to both T-independent and T-dependent antigens in vivo - Partially reversed cachexia, reversed T-cell lymphopenia, corrected defective T-cell proliferation, and decreased sXbp1 expression when administered during pet-store microbial exposure in vivo - Had no significant effect on wild-type control mice (supporting specificity of the rescue to the mutant genotype) (All: Bainter et al. 2021, PMID:33529166.)

TUDCA is an FDA-approved-adjacent compound in other contexts (it is marketed/used off-label as a chemical chaperone in some settings), but no human clinical trial of TUDCA specifically for IMD128/COPG1 deficiency was found in this search — this represents a clear translational-research gap rather than an established therapy. Suggested NCIT candidate if curated as an experimental treatment: NCIT:C15986 (Pharmacotherapy) with therapeutic_agent bound to a CHEBI term for tauroursodeoxycholic acid (CHEBI ID not independently verified in this session).

Treatment strategy note for KB curation: Given the strength of the mechanistic rescue data, this disease is a strong candidate for a mechanistic_hypotheses/discussions entry (kind: KNOWLEDGE_GAP or a treatment-hypothesis framing) noting that TUDCA and other UPR-modulating agents represent a mechanistically grounded but clinically untested therapeutic avenue — this should be explicitly flagged as preclinical/model-organism evidence (evidence_source: MODEL_ORGANISM and IN_VITRO as appropriate, split by evidence item per the mixed-source rule) and not conflated with an approved human treatment.

13. Prevention

No primary, secondary, or tertiary prevention strategies specific to IMD128 were found. As an autosomal recessive monogenic disease identified in a consanguineous family, the only directly applicable prevention modalities are the general ones applicable to any newly characterized recessive disorder: - Genetic counseling for the family and extended consanguineous kindred regarding recurrence risk (25% for each future pregnancy of carrier parents) — NCIT:C15240 (Genetic Counseling) - Carrier screening / prenatal or preimplantation genetic testing could in principle be offered to the family once the causal variant is known, though no report of this being implemented was found - Cascade/family testing of at-risk relatives given the consanguineous pedigree structure

No population-level newborn screening, vaccination strategy, or public-health intervention exists for this condition, consistent with its status as a single-family, recently discovered ultra-rare disease.

14. Other Species / Natural Disease

Taxonomy: No naturally occurring veterinary/animal disease caused by spontaneous COPG1 mutation was identified in the search (no OMIA entry found in this session). NCBI Taxon: Homo sapiens (NCBITaxon:9606) is the only species with reported natural disease.

Gene orthologs: Copg1 is highly conserved; mouse ortholog Copg1 (used directly to generate the engineered model below). No comparative/orthology database identifiers were independently retrieved in this session (e.g., specific NCBI Gene ID for mouse Copg1 was not confirmed here).

Natural disease in other species: None reported — this is not a known veterinary disease.

Comparative biology: The mouse model (below) represents an engineered, not naturally occurring, disease model, but demonstrates strong evolutionary conservation of the underlying γ1-COP/KDELR/UPR mechanism between mouse and human.

15. Model Organisms

Genetic model: CRISPR/Cas9-generated Copg1^K652E knock-in mouse, homozygous for the orthologous patient mutation, engineered specifically to recapitulate the human disease (Bainter et al. 2021, PMID:33529166). This is a precise, patient-variant-matched knock-in model (not a knockout), directly testing the pathogenicity and mechanism of the identified human allele.

Phenotype recapitulation: - Under SPF (low pathogen exposure) conditions: normal lymphocyte development/numbers, normal T-cell proliferation, but hypogammaglobulinemia and defective antibody responses — a partial/subclinical recapitulation. - Under naturalistic microbial exposure (pet-store mouse cohousing, 22 days): progressive weight loss (to ~70% baseline), T-cell lymphopenia (CD3+, CD4+, CD8+), severely impaired T-cell proliferation, hypergammaglobulinemia, and elevated pro-inflammatory cytokines (TNF-α, IFN-γ, IL-6) — a much closer recapitulation of the overt human clinical phenotype (though the human patients had hepatitis and bronchiectasis, which are not described as reproduced in the mouse model in the material retrieved). - Mechanistically, the mouse model reproduced the key cellular findings from human patient cells: increased ER stress markers (sXbp1, Hspa5/BiP, CHOP) in activated T and B cells, and increased T-cell apoptosis upon activation.

Model limitations: The SPF-housed mouse alone substantially underrepresents disease severity relative to the human phenotype, which is itself the paper's key insight (motivating the environmentally "dirty" cohousing paradigm to unmask the phenotype) — i.e., standard SPF vivarium conditions are explicitly identified as a limitation for recapitulating this particular immunodeficiency. No mouse data on hepatitis, bronchiectasis, or mortality were reported in the material retrieved, so the pulmonary/hepatic end-organ damage seen in human patients is not clearly reproduced (or at least was not described in the summary I retrieved) — flag as an unconfirmed gap rather than asserting either a positive or negative finding without checking the full paper.

Other model systems: - Patient-derived skin fibroblasts were used to demonstrate impaired retrograde COPI transport (increased colocalization of a VSVGts-KDELR fusion reporter with the Golgi marker GM130) — an in vitro human cellular model directly from affected individuals, valuable for confirming variant pathogenicity independent of the mouse system. - No zebrafish, Drosophila, C. elegans, yeast, iPSC, or organoid models of COPG1 deficiency were identified in the sources retrieved for this session.

Research applications: The mouse model is directly useful for studying (1) the UPR/ER-stress mechanism of lymphocyte-restricted immunodeficiency, (2) gene-by-environment interaction in primary immunodeficiency severity, and (3) preclinical testing of ER-stress-modulating therapeutics (TUDCA), as already demonstrated.

Resources: No specific repository/stock number (JAX, MMRRC, IMSR) for the Copg1^K652E mouse line was found in the search results retrieved in this session — this should be checked directly against IMSR/MGI before citing a specific resource identifier.

Summary of Key Gaps and Verification Needs (for curator follow-up)

This report should be treated as a lead, per this repository's evidence-discipline rules — every CURIE, exact quote, and identifier above needs independent verification before being written into a KB YAML file: 1. OMIM full Clinical Synopsis text was not directly retrievable (403 error) — re-fetch from omim.org or via an authenticated/cached source before finalizing phenotype frequencies and any additional clinical detail. 2. gnomAD constraint metrics (pLI/LOEUF) for COPG1, and population allele frequency for the specific c.1954A>G variant, were not found/confirmed in this session. 3. ClinVar classification of the variant was not independently confirmed. 4. Exact human clinical management (IVIG, antimicrobial prophylaxis, HSCT) for the 5 index patients was not confirmed from the sources retrieved — do not assume standard CID management was actually used for this family without checking the JCI full text/methods. 5. Sex distribution and precise ages/follow-up duration of the 4 surviving siblings were not confirmed. 6. MONDO:0975834 mapping was taken from the task's own stub metadata and not independently cross-checked against a live MONDO release in this session. 7. Transcript reference (e.g., NM_ accession) for the c.1954A>G nomenclature was not independently confirmed.

All quoted material above in quotation marks is copied directly, as reported by the fetched source, from the JCI article's text (via WebFetch summarization) or from search-engine-generated summaries of PubMed/JCI content — these are AI-mediated retrievals of the primary source, not my own reading of the original PDF, and should be re-verified against the original JCI article text (open access: https://www.jci.org/articles/view/140494) before being used as an exact-quote snippet: in KB evidence items, per this repository's rule that a snippet must be an exact source substring verified at curation time, not a paraphrase relayed through an intermediate tool.

Sources

Reference Validation

Checked with linkml-reference-validator 0.3.0rc1.

Outcome Count
References checked 4
Resolved 4
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 1
Quoted claims found in source 0
Quoted claims not found in source 1
References weighed for topical relevance 4
On topic 4
Off topic 0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

  • PMID:33529166 (abstract only): "a salt bridge between K652 and the carboxyl side chain of E757 and a hydrogen bond between K652 and the main chain carbonyl oxygen of D762"
  • Text part not found as substring: 'a salt bridge between K652 and the carboxyl side chain of E757 and a hydrogen bond between K652 and the main chain carbonyl oxygen of D762' (note: only abstract available for PMID:33529166, full text may contain this excerpt)

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 40
Resolved 39
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1
Terms whose name was checked 17
Terms named correctly 15
Terms named as a different term 1
Terms whose name is worth a second look 1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • HP:0032179 (1 mention) - the report calls it "verify exact CD8 lymphopenia term"; HP calls it Abnormal circulating globulin concentration

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • GO:0006890 (1 mention) - the report calls it "retrograde vesicle-mediated transport, Golgi to ER"; GO calls it retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum, and lists "retrograde vesicle-mediated transport, Golgi to ER" among its other names