Abstract
Background
COPA syndrome is a recently described and rare monogenic autosomal dominant disease caused by heterozygous missense mutations in the Coatomer Protein Subunit alpha (COPA) gene that encodes the alpha subunit of coat protein complex I (COPI). Its main clinical manifestations are inflammatory lung disease, arthritis, and renal disease. The development of inflammation in COPA syndrome maybe due to abnormal autophagic response and abnormal activation of type I interferon pathway. To date, 59 cases of COPA have been reported worldwide.
Methods
In this case, Trio‐whole exome sequencing was employed in the proband and her parents to identify the underlying genetic cause. COPA variant were detected and the clinical presentation of the patient was described.
Results
Herein, we report a case of a 5‐year‐old girl with COPA syndrome who presented with symptoms of arthritis combined with Anti‐neutrophil Cytoplasmic Antibody (ANCA) associated vasculitis (AAV), and progressive renal decline with minimal pulmonary involvement. Trio‐whole exome sequencing was performed which revealed a novel heterozygous likely pathogenic variation in the COPA gene (c.679C>T,p.Arg227Cys), which was maternally inherited. Her mother was a heterozygote, but she had no phenotypic manifestations. No other mutations associated with the clinical phenotype were identified.
Conclusion
The present identification and characterization of a novel mutation expands the genotypic spectra of the COPA syndrome and provide reference data to guide future clinical diagnosis and treatment of COPA syndrome.
Keywords: ANCA‐associated vasculitis, arthritis, COPA syndrome, novel gene variant
We report a case of a 5‐year‐old girl with COPA syndrome who presented with symptoms of arthritis combined with ANCA‐associated vasculitis (AAV), and rapidly progressive renal decline with minimal pulmonary involvement.
Trio‐whole exome sequencing identified a novel heterozygous pathogenic variation in the COPA gene (c.679C>T,p.Arg227Cys).
The identification and characterization of the novel mutation expands the genotypic spectrum of COPA syndrome and provide reference data for guiding future clinical diagnosis and treatment of COPA syndrome.
1. INTRODUCTION
COPA syndrome is a monogenic autosomal dominant disease caused by heterozygous missense mutations in the Coatomer Protein Subunit alpha (COPA) gene that encodes the alpha subunit of coat protein complex I (COPI). COPA is a cytoplasmic protein complex, which binds to the bilysine motif and reversibly combines with non‐clathrin‐coated vesicles (CCV) of the Golgi complex. It mediates retrograde trafficking from Golgi complex to the endoplasmic reticulum (ER). The COPA syndrome was first reported in 2015, and its primary clinical manifestations include autoimmune lung disease, arthritis, and renal disease (Watkin et al., 2015). To date, 59 cases of the condition have been reported worldwide (Frémond & Nathan, 2021). In this article, we report a case of the COPA syndrome in a child, likely caused by an unreported novel gene mutation (NM_001098398) c.679C>T, p.Arg227Cys. Our findings expand the genotypic spectra of the COPA syndrome and provide reference data to guide future clinical diagnosis and treatment of COPA syndrome.
2. METHODS
Informed assent and consent were obtained from the patient and her parents. DNA was extracted from peripheral venous blood samples obtained from the patient and her parents. The trio (parents and proband) samples were then subjected to whole‐exome sequencing (WES) at the Chigene Translational Medicine Research Center Co., Ltd., Beijing. The xGen Exome Research Panel v2.0 (IDT, Iowa, USA) was used to capture the whole exome. Sequencing was conducted on the DNBSEQ‐T7 platform (BGI, China) following standardized protocols. The paired‐end reads were performed using Burrows–Wheeler Aligner (BWA) to the Ensemble GRCh37/hg19 reference genome. Base quality score recalibration together with SNP and short indel calling was carried out using GATK. Several databases for MAFs annotation including 1000 genomes, dbSNP, ESP, ExAC, and Chigene in‐house MAFs database were analyzed. Bioinformatics tools such as PolyPhen, Mutation Taster, REVEL, and CADD were employed to predict the pathogenicity of genetic variants. Finally, the variants were classified according to the guidelines provided by the American College of Medical Genetics and Genomics (ACMG).
The predicted structure of COPA (PDB: AF‐P53621‐F1) was downloaded from the AlphaFold Protein Structure Database (https://alphafold.ebi.ac.uk/). The constructed model structure was visualized and analyzed using PyMOL software (www.pymol.org).
2.1. Clinical features
A 5‐year‐old girl visited our hospital due to joint swelling and pain that had been persistent for more than four months. The joint lesions mainly involved the interphalangeal joint of the left first toe, the right ankle joint, and the left wrist joint. The patient exhibited limited joint movement without any signs of redness, swelling, or heat. Furthermore, she had no history of contact with animals such as sheep, cattle, or infectious diseases. Laboratory examination showed elevated levels of C‐reactive protein (CRP) and erythrocyte sedimentation rate (ESR) and high levels of positive rheumatoid factor and anti‐cyclic peptide containing citrulline (anti‐CCP). Joint ultrasound examination suggested synovial hyperplasia and Color Doppler flow imaging (CDFI) detection of blood flow revealed joint cavity effusion. Based on our initial assessment, brucellosis, tuberculosis, Wilson's disease, hypothyroidism, calcium and phosphate metabolic disorders, common space‐occupying lesions and hematologic neoplastic diseases were ruled out. These findings initially suggested the presence of juvenile idiopathic arthritis (Table 1). Therefore, the patient was administered with oral methotrexate and non‐steroidal anti‐inflammatory drugs (NSAIDs). During hospitalization, laboratory tests showed that pANCA and anti‐myeloperoxidase antibodies (MPO) were positive. The child had no signs of SKLEN (Skin, Kindey, Lung, Ear, Nose and Throat (ENT), Nerve) involvement except for slight inhomogeneity and a few scattered faint patches and small nodular shadows on the chest computed tomography (CT) scans (Figure 1). Because ANCA‐associated vasculitis (AAV) had not been ruled out, routine urinalysis and renal function were monitored dynamically.
TABLE 1.
Baseline laboratory characteristics of the patient.
| Variable | Reference range | |
|---|---|---|
| Peripheral blood cells | ||
| White blood cells (×109 /L) | 8.57 | 3.5–9.5 |
| Percentage of neutrophils (%) | 60.2 | 42.3–71.5 |
| Red blood cells (×1012/L) | 4.0 | 4–4.5 |
| Hemoglobin (g/L) | 120 | 120–140 |
| Platelets (×109 /L) | 466 | 135–350 |
| Blood chemistry | ||
| C‐reactive protein (mg/L) | 11.70 | 0–8 |
| Erythrocyte sedimentation rate (mm/h) | 61 | 0–20 |
| Creatinine (umol/L) | 34.1 | |
| Urea nitrogen (umol/L) | 5.78 | |
| Serology | ||
| Rheumatoid factor | 257 | 10–30 |
| Anti‐cyclic peptide containing citrulline (anti‐CCP) | Strongly positive | Negative |
| Anti‐neutrophil Cytoplasmic Antibody (ANCA) | ||
| pANCA | Positive | Negative |
| cANCA | Negative | Negative |
| anti‐myeloperoxidase antibodies (MPO) | Positive | Negative |
| Antiproteinase 3 antibody (PR3) | Negative | Negative |
| Anti‐RA33 antibody | Negative | Negative |
| Human leucocyte antigen B27(HLA‐B27) | Negative | Negative |
| Immunoglobulin G (g/L) | 8.52 | 4.81–12.2 |
| Immunoglobulin A (g/L) | 2.23 | 0.42–1.58 |
| Immunoglobulin M (g/L) | 2.5 | 0.41–1.65 |
| Complement 3 (g/L) | 0.86 | 0.74–1.4 |
| Complement 4 (g/L) | 0.171 | 0.12–0.36 |
| Anti‐nuclear antibodies | Negative | Negative |
| Serum krebs von den lungen‐6 (KL‐6) | Negative | Negative |
| Pathogen | ||
| B. burgdorferi antibody | Negative | Negative |
| Tuberculosis spot test | Negative | Negative |
| Routine urine test | ||
| Specific gravity | 1.025 | 1.003–1.030 |
| Protein | Negative | Negative |
| Red blood cells (per HPF) | 1.70 | 0–3 |
| Others | ||
| Ceruloplasmin | 0.388 | 0.31–0.55 |
| Serum calcium | 2.22 | 2.2–2.7 |
| Serum phosphorus | 1.52 | 1.2–1.9 |
| Parathyroid hormone (PTH) | 15.86 | 15–65 |
| Thyroid hormone 3 | 5.83 | 2.43–6.01 |
| Thyroid hormone 4 | 16.01 | 9.01–19.05 |
| Thyroid stimulating hormone | 0.36 | 0.3–4.8 |
FIGURE 1.
Pulmonary CT scans. (a) At first admission (b) 3 months after the first discharge and before the second admission; (c) before the second discharge, about 2 weeks after (b).
Three months after first discharge, the child developed mild proteinuria and showed symptoms of haematuria (red blood cells (RBC) 156/High power field (HPF) and urine protein 1+). Three weeks later, her creatinine levels rose from 36.9 umol/L to 52.2 umol/L and chest CT scans showed progressive signs of significantly scattered faint patches and nodular shadows (Figure 1b). Based on results of renal pathology, we suspected necrotizing crescentic nephritis, which is consistent with the diagnosis of MPO‐ANCA‐associated glomerulonephritis (Figure 2). Thus, the patient was treated with intravenous methylprednisolone (2 mg/Kg/die) followed by pulse therapy of 15 mg/kg/d of methylprednisolone for 3 days and cyclophosphamide treatment of 10 mg/kg/d for 2 days. However, the kidney function continued to deteriorate as indicated by elevated creatinine (114.8 umol/L), low Glomerular filtration rate (GFR) (L‐GFR: 15.2 mL/min, R‐GFR: 21.5 mL/min), and increased RBCs (825/HP), and high secretion of protein in urine (2+, 1.54 g/24 h). We administered rituximab at a dose of 375 mg per square meter of body‐surface area once week after cyclophosphamide (Figure 3). This treatment decreased the creatinine levels slightly (to 92.8 umol/L) and the results of chest CT scans revealed significant improvement (Figure 1). Oral methylprednisolone was administered as maintenance treatment after discharge. Based on the aforementioned clinical manifestations, Type I interferon disease was suspected, particularly COPA syndrome.
FIGURE 2.
Renal pathology. (a) H.E (400X), (b) P.A.S, (400X), (c) P.A.S.M (400X) of Light microscopy showing a total of 7 glomeruli at all levels, 3 with cellular crescents, and 1 with cellular fibrous crescents. The rest of the glomeruli were mildly altered, with good opening of capillary loop and no obvious changes in the mesangial region. The visceral epithelial cells and the parietal epithelial cells were swollen, and some of the balloon walls of the glomeruli were thickened and delaminated. Granular and vacuolar degeneration of renal tubular epithelium; focal (20%) infiltration of lymphocytes, monocytes, and a few neutrophils and eosinophils in the interstitium; some tubular atrophy and loss of structure; and focal (10%) interstitial edema were seen. No significant changes were seen in the small arteries. (d) Electron microscopy showing mild glomerular changes, well opened capillary loops, no mesangial cell hyperplasia, increased mesangial matrix, scattered electron dens in the mesangial region, normal basement membrane thickness, no widening of the internal laminae of the basement membrane, no uneven thickness, delamination, or arachnoid of basement membrane, and segmental pedicle fusion. Mitochondrial swelling and endoplasmic reticulum expansion in renal tubular epithelium, thickening of basement membrane in some tubules, infiltration of inflammatory cells (monocytes and lymphocytes, and a few neutrophils) in the interstitium, and interstitial edema were seen. No small arteries were seen. (e) Immunofluorescence showing IgG (±), IgA (−), IgM (−), C1q (−), C3 (±), Fib (−).
FIGURE 3.
Treatment and follow‐up of the patient.
2.2. Genetic analysis
Subsequently, trio‐based whole exome sequencing was performed which identified a heterozygous missense variation: chr1:160293248, c.679C>T,p.Arg227Cys. The WES filtering steps are summarized in Table S1. The mutation was located in the anaphase‐promoting complex subunit 4 WD40 domain (Figure 4). This variant has not been reported in the ExAC, dbSNP, and gnomAD databases. Using the Variant effect prediction software (SIFT, Polyphen‐2, Provean, REVEL, CADD, and MutationTaster), the p.Arg227Cys variant was predicted to be deleterious (Provean score of −7.75, deleterious; M‐CAPscore of 0.06307, damaging; REVEL score of 0.537, deleterious; CADD score of 31, deleterious; PolyPhen score of 1, probably damaging; MutationTaster score of 1, disease causing; SIFT score of 0, damaging). The computer hazard predictions of the variant are in Table S2. p.Arg227Cys was considered to be likely pathogenic (PM1 + PM2 + PP2 + PP3) based on the ACMG guidelines. Moderate evidence of pathogenicity: PM1, is located in a mutational hot spot and/or critical and well‐established; PM2, the variant is not available in all population databases. Supporting evidence of pathogenicity: PP2, missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PP3, multiple lines of computational evidence support a deleterious effect on the gene or gene product. The mutation was maternally inherited because her mother was a heterozygote, although she had no phenotypic manifestations and negative results of the analysis of the urine and chest CT. Sequence alignment results showed that Arg227 and surrounding residues in COPA are conserved in vertebrates. The Arg227Cys substitution changed the charge of the protein and thus may have disrupted the function of the region (Figure 5).
FIGURE 4.
(a) Genetic analysis: Trio‐based whole exome sequencing showing a heterozygous variation in the eighth exon of the COPA gene (c.679C>T,p.Arg227Cys) in the patient and her mother. (b) domain: Green: WD40 repeat domain, Red: Anaphase‐promoting complex subunit 4 WD40 domain, Blue: Coatomer WD associated region, Yellow: Coatomer (COPI) alpha subunit C‐terminus.
FIGURE 5.
Electrostatic potential diagram: negative and positive charges are shown in red and blue.
Based on this diagnosis, we gave her a second dose of rituximab at the three months later, with the B cell count of 5 at that time. At the same time tofacitinib was added to her treatment regimen. Eight weeks later, her ANCA and Rheumatoid factor (RF) tests were negative. Further follow up found that the patient has no joint swelling, her chest CT scans (before the second discharge and 4 months after second discharge) are normal, serum tests for ANCA and RF are negative, CRP and ESR are normal, but the anti‐CCP is positive. Serum creatinine is 58.2 umol/L and urine protein is 0.69 g/24 h.
3. DISCUSSION
COPA syndrome is a rare Mendelian monogenic autosomal dominant disorder that was first reported in 2015. Its clinical symptoms are caused by impairment of retrograde transport of protein vesicles from the Golgi complex to the ER. This impairment increases mRNA protein translation resulting in ER stress and immune dysregulation. COPA mutations upregulate the levels of T‐helper 17 (TH17) cells, which in turn changes in levels of inflammatory cytokines (Interleukin (IL)‐1β, IL‐6). Moreover, patients showed increased expression of interferon‐stimulated genes, enhanced response of STING pathway, and the imbalance of inflammatory response (Deng et al., 2020; Lepelley et al., 2020; Mukai et al., 2021; Volpi et al., 2018). COPA syndrome is a type I interferon disease, and the development of inflammation in COPA syndrome maybe due to the abnormal activation of the type I interferon pathway. In this case, the levels of inflammatory cytokines were not monitored in the initial stages of treatment and hence correlation analysis could not be carried out.
To date, 14 missense substitutions associated with COPA syndrome have been reported, including p.Pro145Ser (He et al., 2018), p.Lys230Asn, p.Arg233His, p.Ala239Pro (Watkin et al., 2015), Trp240Arg, Trp240Ser, Trp240Leu, p.Glu241Lys, p.Glu241Ala (Taveira‐DaSilva et al., 2019), p.Val242Ala (Lin et al., 2020), p.Val242Gly (Kato et al., 2021), p.Asp243Asn, p.Asp243Gly, and p.Arg281Trp (Zeng et al., 2021). All these mutations are located in exon 6/8/9 of chromosome‐1. The Arg227Cys substitution changes the charge on the protein and thus may disrupt the function of the region.
Notably, COPA gene mutation do not affect the overall expression level of COPα protein in cells, but impairs its normal function. It is hypothesized that these tissues are either more sensitive to the mutation and its impact on intracellular traffic or more sensitive to the resulting pro‐inflammatory environment that these mutations induce. COPA syndrome is characterized by incomplete penetrance and variable expression. The mother of the child in our case study is also a carrier of the mutated gene but did not exhibit any clinical manifestations. The reason for incomplete penetrance are not understood. Gender, or other genetic and environmental factors, may also determine whether carriers of COPA mutant alleles develop clinical disease. It has also been suggested that COPA may require a “second‐hit” to initiate disease onset and/or drive disease progression (Frémond et al., 2019). In our case, the child only showed joint involvement at the initial stages of the disease, specifically the first interphalangeal joint of the left foot, the right ankle joint, and the left wrist joint, which is consistent with the previous reports of the main joints involved (Frémond & Nathan, 2021; Volpi et al., 2018). Inflammatory lung disease with diffuse alveolar hemorrhage is the most common manifestation of COPA syndrome (Tsui et al., 2018; Watkin et al., 2015). Of the 59 patients with COPA syndrome reported to date, 25% did not present with symptoms of lung disease, while 55% did not present with acute lung hemorrhage. Lung manifestations in the present child were currently mild, with only a few interstitial changes as detected in chest CT scans. However, since the disease is progressive, and the patient is only 5 years old, long‐term follow‐up is required to determine if the lesions will worsen or become fibrotic in the future. We postulate that early treatment of JAK inhibitors can improve and reduce pulmonary involvement.
COPA syndrome is an inflammatory disease characterized by elevated levels of inflammatory markers such as CRP and ESR and an autoimmune disease manifested by positive antinuclear antibodies (ANA), RF, and MPO/PR3 ANCAs (Vece et al., 2016). Our patient was positive for RF, anti‐CCP, MPO, and pANCA. It is easy for clinicians to diagnose a patient with Idiopathic juvenile arthritis (JIA) overlapping AAV or Systemic lupus erythematosus (SLE) when the patient is positive for RF and CCP, even if ANCA or ANA are positive. In our case, before the diagnosis of COPA symdrome, given the lung and kidney complications, renal insufficiency, and the child's elevated levels of ANCA antibody and RF, we initiated a two‐day course of intravenous cyclophosphamide (10 mg/kg.d) and rituximab (375 mg/m2) following the ANCA‐related vasculitis guidelines. Later, the genetic results confirmed the diagnosis of COPA syndrome, and we developed a subsequent treatment plan based on this diagnosis. Taking into account the child's age, the population density of Northeast China, and the infection risk, along with insights from past cases, we inferred that B‐cell recovery typically occurs around 3–6 months. The optimal timing for its application is at the 3‐month mark, as this tends to yield the most favorable outcomes. Therefore, we gave her a second dose of rituximab three months after the first administration, with the B cell count of 5 at that time.
The recent advancement in medical research has led to the recognition of type I interferon‐induced pathology. A proper recognition of type one interferonopathy is the potential clue to the initiation of appropriate treatment. Considering that abnormal activation of the type I interferon pathway contributes to the pathogenesis of COPA syndrome (Lepelley et al., 2020), JAK inhibitors may have beneficial effects on patients. Recent case reports indicate that JAK inhibitors have good clinical short‐term effects and are associated with interferon (IFN) scores in patients with COPA syndrome (Frémond et al., 2019; Kato et al., 2021; Krutzke et al., 2019). But there is no guideline and evidence to support its clinical use and is therefore used as off‐label medication. Based on China's national conditions, off‐label drug reporting is required. Therefore, JAK inhibitors was used 3 months after the diagnosis of the disease. Our case was treated with tofacitinib and has good clinical outcomes at the current follow‐up of 5 months. However, the therapeutic effects of tofacitinib and rituximab are hard to clarify at the moment because the patient had been administered rituximab in the early stages of the disease.
4. CONCLUSION
Young patients with positive autoantibodies, arthritis and multiple organ involvement such as pulmonary and renal involvement, should be screened for COPA syndrome. Early gene detection and an aggressive treatment approach is recommended especially for patients with early onset of the disease. The clinical evolution of COPA syndrome with mutations in different genetic loci may be very different. The present identification and characterization of a novel mutation expands the genotypic spectra of COPA syndrome and provide reference data to guide future clinical diagnosis and treatment of COPA syndrome.
AUTHOR CONTRIBUTIONS
ZY reviewed the literature and participated in manuscript writing. YD and YW participated in acquisition and analysis of the clinical data. GW and LF conducted genetic analysis. CZ revised the manuscript. All authors read and approved the final manuscript.
CONFLICT OF INTEREST STATEMENT
The authors declare that they have no competing interests.
ETHICS STATEMENT
This study was approved by the Ethics Committees of Shengjing hospital of China Medical University and written informed consent was obtained from all patients participating in the study.
Supporting information
Table S1
ACKNOWLEDGMENTS
The authors thank the patient and her family for their participation in this study.
Zheng, Y. , Du, Y. , Wu, Y. , Li, F. , Gu, W. , & Zhao, C. (2024). COPA syndrome caused by a novel p.Arg227Cys COPA gene variant. Molecular Genetics & Genomic Medicine, 12, e2309. 10.1002/mgg3.2309
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
REFERENCES
- Deng, Z. , Chong, Z. , Law, C. S. , Mukai, K. , Ho, F. O. , Martinu, T. , Backes, B. J. , Eckalbar, W. L. , Taguchi, T. , & Shum, A. K. (2020). A defect in COPI‐mediated transport of STING causes immune dysregulation in COPA syndrome. Journal of Experimental Medicine, 217(11), e20201045. 10.1084/jem.20201045 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Frémond, M. L. , Legendre, M. , Fayon, M. , Clement, A. , Filhol‐Blin, E. , Richard, N. , Berdah, L. , Roullaud, S. , Rice, G. I. , Bondet, V. , Duffy, D. , Sileo, C. , Ducou le Pointe, H. , Begueret, H. , Coulomb, A. , Neven, B. , Amselem, S. , Crow, Y. , & Nathan, N. (2019). Use of ruxolitinib in COPA syndrome manifesting as life‐threatening alveolar haemorrhage. Thorax, 75(1), 92–95. 10.1136/thoraxjnl-2019-213892 [DOI] [PubMed] [Google Scholar]
- Frémond, M. L. , & Nathan, N. (2021). COPA syndrome, 5 years after: Where are we? Joint, Bone, Spine, 88, 105070. 10.1016/j.jbspin.2020.09.002 [DOI] [PubMed] [Google Scholar]
- He, T. , Qi, Z. , Luo, S. , Xia, Y. , Li, C. , Huang Y., & Yang, J. (2018). Clinical and genetic analysis of COPA syndrome in one case. Journal of Clinical Pediatrics, 36, 787–790. 10.3969/j.issn.1000-3606.2018.10.015 [DOI] [Google Scholar]
- Kato, T. , Yamamoto, M. , Honda, Y. , Orimo, T. , Sasaki, I. , Murakami, K. , Hemmi, H. , Fukuda‐Ohta, Y. , Isono, K. , Takayama, S. , Nakamura, H. , Otsuki, Y. , Miyamoto, T. , Takita, J. , Yasumi, T. , Nishikomori, R. , Matsubayashi, T. , Izawa, K. , & Kaisho, T. (2021). Augmentation of STING‐induced type I interferon production in COPA syndrome. Arthritis & Rheumatology, 73, 2105–2115. 10.1002/art.41790 [DOI] [PubMed] [Google Scholar]
- Krutzke, S. , Rietschel, C. , & Horneff, G. (2019). Baricitinib in therapy of COPA syndrome in a 15‐year‐old girl. European Journal of Rheumatology, 7(Suppl 1), 1–4. 10.5152/eurjrheum.2019.18177 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lepelley, A. , Martin‐Niclós, M. J. , Le Bihan, M. , Marsh, J. A. , Uggenti, C. , Rice, G. I. , Bondet, V. , Duffy, D. , Hertzog, J. , Rehwinkel, J. , Amselem, S. , Boulisfane‐El Khalifi, S. , Brennan, M. , Carter, E. , Chatenoud, L. , Chhun, S. , Coulomb l'Hermine, A. , Depp, M. , Legendre, M. , … Frémond, M. L. (2020). Mutations in COPA lead to abnormal trafficking of STING to the Golgi and interferon signaling. The Journal of Experimental Medicine, 217(11), e20200600. 10.1084/jem.20200600 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lin, K. Z. , Zhang, F. F. , & Xiao, J. H. (2020). A pathogenic mutation in the COPA gene causes a family of COPA syndrome. Zhonghua Er Ke Za Zhi, 58, 58–59. 10.3760/cma.j.issn.0578-1310.2020.01.015 [DOI] [PubMed] [Google Scholar]
- Mukai, K. , Shum, A. , & Taguchi, T. (2021). Homeostatic regulation of STING by retrograde membrane traffic to the ER. The FASEB Journal, 35(S1), 61. 10.1096/fasebj.2021.35.S1.01855 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Taveira‐DaSilva, A. M. , Markello, T. C. , Kleiner, D. E. , Jones, A. M. , Groden, C. , Macnamara, E. , Yokoyama, T. , Gahl, W. A. , Gochuico, B. R. , & Moss, J. (2019). Expanding the phenotype of COPA syndrome: A kindred with typical and atypical features. Journal of Medical Genetics, 56, 778–782. 10.1136/jmedgenet-2018-105560 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tsui, J. L. , Estrada, O. A. , Deng, Z. , Wang, K. M. , Law, C. S. , Elicker, B. M. , Jones, K. D. , Dell, S. D. , Gudmundsson, G. , Hansdottir, S. , Helfgott, S. M. , Volpi, S. , Gattorno, M. , Waterfield, M. R. , Chan, A. Y. , Chung, S. A. , Ley, B. , & Shum, A. K. (2018). Analysis of pulmonary features and treatment approaches in the COPA syndrome. ERJ Open Research, 4, 1–10. 10.1183/23120541.00017-2018 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Vece, T. J. , Watkin, L. B. , Nicholas, S. K. , Canter, D. , Braun, M. C. , Guillerman, R. P. , Eldin, K. W. , Bertolet, G. , McKinley, S. D. , de Guzman, M. , Forbes, L. R. , Chinn, I. , & Orange, J. S. (2016). Copa syndrome: A novel autosomal dominant immune dysregulatory disease. Journal of Clinical Immunology, 36(4), 377–387. 10.1007/s10875-016-0271-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Volpi, S. , Tsui, J. , Mariani, M. , Pastorino, C. , Caorsi, R. , Sacco, O. , Ravelli, A. , Shum, A. K. , Gattorno, M. , & Picco, P. (2018). Type I interferon pathway activation in COPA syndrome. Clinical Immunology: The Official Journal of the Clinical Immunology Society, 187, 33–36. 10.1016/j.clim.2017.10.001 [DOI] [PubMed] [Google Scholar]
- Watkin, L. B. , Jessen, B. , Wiszniewski, W. , Vece, T. J. , Jan, M. , Sha, Y. , Thamsen, M. , Santos‐Cortez, R. L. , Lee, K. , Gambin, T. , Forbes, L. R. , Law, C. S. , Stray‐Pedersen, A. , Cheng, M. H. , Mace, E. M. , Anderson, M. S. , Liu, D. , Tang, L. F. , Nicholas, S. K. , … Shum, A. K. (2015). COPA mutations impair ER‐Golgi transport and cause hereditary autoimmune‐mediated lung disease and arthritis. Nature Genetics, 47(6), 654–660. 10.1038/ng.3279 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zeng, J. , Hao, J. , Zhou, W. , Zhou, Z. , & Miao, H. (2021). Novel mutation c.841C>T in COPA syndrome of an 11‐year‐old boy: A case report and short literature. Review, 9(24), 1–6. 10.3389/fped.2021.773112 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.