COPA Syndrome (Ala239Pro) Presenting with Isolated Follicular Bronchiolitis in Early Childhood: Case Report

Psarianos, Pamela; Kwan, Jennifer; Dell, Sharon; Wee, Wallace; Rey-McIntyre, Katrina; Chen, Haiying; Dissanayake, Dilan; Laxer, Ronald M.; Shum, Anthony K.; Liu, Feifei; Yip, Kenneth W.

doi:10.1007/s10875-021-01082-8

Cited by 6 publications

(4 citation statements)

References 5 publications

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“…To date, most of the pathogenic COPA variants identified in patients with autoinflammatory diseases compatible with COPA syndrome are located in the 14 amino acid region and the WD40 domain with important functions, except for 4 mutations, that is c.433C > T (p.P145S) (3), c.596A > G (p.H199R) (4), c.841C > T (p.R281W) (5) and c.855G > C (p.Q285H) (6). The genetic testing of this patient revealed a variant of c.715G > C (p.A239P), located within the WD40 domain, which has been previously reported by Pamela Psarianos (7). Clinically, COPA syndrome mainly manifests diffuse alveolar hemorrhage or interstitial lung disease, arthritis, and renal injury.…”

Section: Discussionsupporting

confidence: 69%

“…It is reported that the application of JAK inhibitors can improve the patient's well-being and quality of life of the patients ( 16 , 17 ). Glucocorticoid combined with hydroxychloroquine and mycophenolate mofetil (MMF) can also alleviate cough in COPA patients ( 7 ). In addition, Guan Y et al ( 2 ) reported that two cases of COPA syndrome were treated with sirolimus and achieved favourable therapeutic effect.…”

Section: Discussionmentioning

confidence: 99%

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Case report: COPA syndrome with interstitial lung disease, skin involvement, and neuromyelitis spectrum disorder

Tao

Zhang

et al. 2023

Front. Pediatr.

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This report describes a case of a 22 months Chinese boy with COPA syndrome bearing the c.715G > C (p.A239P) genotype. In addition to interstitial lung diseae, he also suffered from recurrent chilblain-like rashes, which has not been previously reported, and neuromyelitis optica spectrum disorder (NMOSD), which is a very rare phenotype. Clinical manifestations expanded the phenotype of COPA syndrome. Notably, there is no definitive treatment for COPA syndrome. In this report, the patient has achieved short-term clinical improvement with sirolimus.

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Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Case report: COPA syndrome with interstitial lung disease, skin involvement, and neuromyelitis spectrum disorder

Tao

Zhang

et al. 2023

Front. Pediatr.

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“…This condition displays incomplete penetrance. Seventy-five patients with mutations in the N-terminal domain of COPA have been described until now, with great variability in terms of both age of onset and clinical severity (15,16,(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33). The mutations do not affect COPA protein expression, but they impair the retrograde Golgi-to-ER retrieval of dilysine-tagged ER-resident proteins, such as surfeit locus protein 4 (SURF4) and, indirectly, stimulator of interferon genes (STING) (17,34,35).…”

Section: Introductionmentioning

confidence: 99%

Heterozygous mutations in the C-terminal domain of COPA underlie a complex autoinﬂammatory syndrome

Delafontaine,

Iannuzzo,

Bigley

et al. 2024

Journal of Clinical Investigation

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Mutations in the N-terminal WD40 domain of coatomer protein complex subunit α (COPA) cause a type I interferonopathy, typically characterized by alveolar hemorrhage, arthritis, and nephritis. We described 3 heterozygous mutations in the C-terminal domain (CTD) of COPA (p.C1013S, p.R1058C, and p.R1142X) in 6 children from 3 unrelated families with a similar syndrome of autoinflammation and autoimmunity. We showed that these CTD COPA mutations disrupt the integrity and the function of coat protein complex I (COPI). In COPA R1142X and COPA R1058C fibroblasts, we demonstrated that COPI dysfunction causes both an anterograde ER-to-Golgi and a retrograde Golgi-to-ER trafficking defect. The disturbed intracellular trafficking resulted in a cGAS/STING-dependent upregulation of the type I IFN signaling in patients and patient-derived cell lines, albeit through a distinct molecular mechanism in comparison with mutations in the WD40 domain of COPA. We showed that CTD COPA mutations induce an activation of ER stress and NF-κB signaling in patient-derived primary cell lines. These results demonstrate the importance of the integrity of the CTD of COPA for COPI function and homeostatic intracellular trafficking, essential to ER homeostasis. CTD COPA mutations result in disease by increased ER stress, disturbed intracellular transport, and increased proinﬂammatory signaling.

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“…As discussed above, multiple groups have not only shown a role for type I IFN in driving the pathology of COPA but have also shown that failure to relocate STING from the Golgi post activation results in overactivation of STING-induced IFN induction. [ 51 , 52 , 69 , 70 , 71 , 72 , 131 , 132 , 133 , 134 ] Recent work has also shown that C9orf72, a protein associated with the development of amyotrophic lateral sclerosis (ALS), regulates STING stability and that the absence of C9orf72 results in STING-induced inflammatory disease. [ 135 ] Thus, enhanced exposure to cytosolic DNA through incomplete DNA degradation in the case of AGS or a reduction in activity of DNA repair pathways targeting oxidized lesions, or lack of regulation of STING may contribute to enhanced signaling through the cGAS-STING pathway in SLE.…”

Section: Introductionmentioning

confidence: 99%

Regulation of cGAS-STING pathway - Implications for systemic lupus erythematosus

Hagiwara

Moore

Wallace

et al. 2021

Rheumatology and Immunology Research

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Type I interferon (IFN-I) is implicated in the pathogenesis of systemic lupus erythematosus (SLE) and the closely associated monogenic autoinflammatory disorders termed the “interferonopathies.” Recently, the cytosolic DNA sensor cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) and its downstream signaling adaptor stimulator of interferon genes (STING) have been identified as having important, if not central, roles in driving IFN-I expression in response to self-DNA. This review highlights the many ways in which this pathway is regulated in order to prevent self-DNA recognition and underlines the importance of maintaining tight control in order to prevent autoimmune disease. We will discuss the murine and human studies that have implicated the cGAS-STING pathway as being an important contributor to breakdown in tolerance in SLE and highlight the potential therapeutic application of this knowledge for the treatment of SLE.

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COPA Syndrome (Ala239Pro) Presenting with Isolated Follicular Bronchiolitis in Early Childhood: Case Report

Cited by 6 publications

References 5 publications

Case report: COPA syndrome with interstitial lung disease, skin involvement, and neuromyelitis spectrum disorder

Case report: COPA syndrome with interstitial lung disease, skin involvement, and neuromyelitis spectrum disorder

Heterozygous mutations in the C-terminal domain of COPA underlie a complex autoinﬂammatory syndrome

Regulation of cGAS-STING pathway - Implications for systemic lupus erythematosus

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