TY - JOUR
AU - Rawat,, Amit
AB - Rheumatology key message Monogenic causes should be evaluated in children with arthritis and family history or unusual clinical manifestations. DEAR EDITOR, An 11-year-old boy presented with pain and swelling in multiple joints involving ankles, knees, elbows and wrists since the age of 5. He was diagnosed to have juvenile idiopathic arthritis elsewhere and was treated with subcutaneous methotrexate, oral prednisolone and naproxen. However, he gradually developed deformities in several joints. His father also had deforming arthritis since the age of 12 and developed progressive lung disease later. He succumbed to the illness at 38 years of age. On examination, the boy had deformities with decreased range of movement in bilateral wrist and small joints of hands and feet (Fig. 1). The rest of the examination was unremarkable. Laboratory investigations revealed ANA positivity (3+ speckled pattern on indirect immunofluorescence with 1:60 dilution), positive RF (RF+), elevated anti-cyclic citrullinated peptide titres, normal erythrocyte sedimentation rate and normal C-reactive protein (Supplementary Table S1, available at Rheumatology online). Chest X-ray showed prominent bronchovascular markings with few small nodular opacities in bilateral lung fields (Supplementary Fig. S1, available at Rheumatology online). High resolution computed tomography (HRCT) of the chest showed 1–2 mm nodules in centrilobular distribution in bilateral lower lobes with mild septal thickening and areas of mosaic attenuation in superior segment of right lower lobe. X-ray wrist and knee joints showed marked periarticular osteopenia. However, no joint space narrowing or erosions were noted (Supplementary Figs S2 and S3, available at Rheumatology online). X-ray lumbosacral spine showed loss of lumbar lordosis and there were no features suggestive of progressive pseudorheumatoid chondrodysplasia (Supplementary Fig. S4, available at Rheumatology online). A clinical possibility of COPA (coatomer protein complex, subunit alpha (COP-α)) syndrome was considered in view of RF- and ANA-positive early onset deforming arthritis and lung involvement with a family history of arthritis and lung disease in the father, suggestive of an autosomal dominant mode of inheritance. Targeted Sanger sequencing for hotspots reported in the COPA gene (i.e. exon 8 and exon 9) [1] was carried out that revealed a heterozygous splice-site mutation (c.841C>T, p. Arg281Trp) in exon 9 (Supplementary Material section, available at Rheumatology online). Family screening was carried out and one of his paternal aunts was also found to have the same mutation; however, she was asymptomatic. The two siblings of the index patient were not found to have this mutation on Sanger sequencing. Fig. 1 Open in new tabDownload slide Small joints of hand and feet with deformities and swelling. (A) & (B) hand; (C) feet. Fig. 1 Open in new tabDownload slide Small joints of hand and feet with deformities and swelling. (A) & (B) hand; (C) feet. He was initiated on subcutaneous methotrexate (15 mg per week) and physiotherapy. A repeat HRCT chest performed at 2.5 years of follow-up showed an increase in nodular opacities predominantly affecting basal segments of bilateral lower lobes. Worsening of the pulmonary function was also noted on spirometry. He was initiated on oral prednisolone, leflunomide (10 mg/day), thalidomide (100 mg/day) and subcutaneous methotrexate was increased to 20 mg/week. He is clinically well on follow-up; however, deformities of joints are persisting. COPA syndrome has been categorized under autoinflammatory syndromes in the recent International Union of Immunological Societies (IUIS) classification of primary immunodeficiency diseases [2]. It is an autosomal dominant disorder and is characterized by deforming arthritis and lung involvement that is usually in the form of interstitial lung disease or pulmonary haemorrhage [3]. Almost all patients with this syndrome reported until the present date have been found to have heterozygous missense mutations in COPA gene not involving the splice site [4, 5]. Index case had a pathogenic heterozygous splice site mutation in the COPA gene. Although the same mutation has previously been reported in a 9-year-old boy who had follicular bronchiolitis with ANA and ANCA positivity, arthritis was not reported in this patient [6]. As COP-α protein plays a critical role in vesicle transport from Golgi apparatus to endoplasmic reticulum (ER); mutations in COPA gene have been shown to affect this retrograde transport. It has been hypothesized that mutations in COPA gene lead to aberrant egress of proteins from the cells. These proteins are normally programmed to be modified or degraded. This leads to abnormal antigen exposure and ER stress leading to the generation of autoreactive T cells and auto-antibodies and synthesis of proinflammatory cytokines and type I interferons [7, 8]. A recent study on a murine model of COPA syndrome has also demonstrated defective central (thymic) tolerance to be associated with this disease [9]. While joints, lungs and kidneys have been reported to be the primary target in this syndrome, several other organs may also be involved [3–5, 7]. Until present, no definite treatment has been found to be effective for these patients. Patients may respond to immunosuppressant therapy such as corticosteroids, methotrexate, mycophenolate mofetil and cyclophosphamide [4, 5, 7]. Index case was managed with corticosteroids, methotrexate and leflunomide. To conclude, COPA syndrome is a rare genetic cause of arthritis in children. It is prudent to suspect COPA syndrome in children who have RF+ polyarthritis with other auto-antibody positivity and lung involvement with family history suggestive of an autosomal dominant mode of inheritance. Acknowledgements A.Z.B.: writing of initial draft of manuscript, editing and revision of manuscript at all stages of its production, review of literature, drawing of figures; A.K.: contributed to editing of manuscript, performed genetic analysis of the patient, review of literature; A.K.J.: inception of idea, evaluation, management and follow up of the patient and editing of manuscript, critical revision of the manuscript at all stages of production and final approval; P.K.P./S.G.: evaluation and management of the patient, follow up of the patient, editing and approval of the manuscript; A.R.: contributed to editing of manuscript, performed genetic analysis and laboratory evaluation of the patient, revision of the manuscript, final approval of manuscript. Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: The authors have declared no conflicts of interest. Supplementary data Supplementary data are available at Rheumatology online. References 1 Tsui JL , Estrada OA , Deng Z et al. Analysis of pulmonary features and treatment approaches in the COPA syndrome . ERJ Open Res 2018 ; 4 : 00017 – 2018 . Google Scholar Crossref Search ADS PubMed WorldCat 2 Tangye SG , Al-Herz W , Bousfiha A et al. Human inborn errors of immunity: 2019 Update on the classification from the International Union of Immunological Societies Expert Committee . J Clin Immunol 2020 ; 40 : 24 – 64 . Google Scholar Crossref Search ADS PubMed WorldCat 3 Vece TJ , Watkin LB , Nicholas S et al. Copa syndrome: a novel autosomal dominant immune dysregulatory disease . J Clin Immunol 2016 ; 36 : 377 – 87 . Google Scholar Crossref Search ADS PubMed WorldCat 4 Taveira-DaSilva AM , Markello TC , Kleiner DE et al. Expanding the phenotype of COPA syndrome: a kindred with typical and atypical features . J Med Genet 2019 ; 56 : 778 – 82 . Google Scholar Crossref Search ADS PubMed WorldCat 5 Patwardhan A , Spencer CH. An unprecedented COPA gene mutation in two patients in the same family: comparative clinical analysis of newly reported patients with other known COPA gene mutations . Pediatr Rheumatol Online J 2019 ; 17 : 59 . Google Scholar Crossref Search ADS PubMed WorldCat 6 Prenzel F , Harfst J , Schwerk N et al. Lymphocytic interstitial pneumonia and follicular bronchiolitis in children: a registry-based case series . Pediatr Pulmonol 2020 ; 55 : 909 – 17 . Google Scholar Crossref Search ADS PubMed WorldCat 7 Watkin LB , Jessen B , Wiszniewski W et al. COPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis . Nat Genet 2015 ; 47 : 654 – 60 . Google Scholar Crossref Search ADS PubMed WorldCat 8 Volpi S , Tsui J , Mariani M et al. Type I interferon pathway activation in COPA syndrome . Clin Immunol 2018 ; 187 : 33 – 6 . Google Scholar Crossref Search ADS PubMed WorldCat 9 Deng Z , Law CS , Ho FO et al. A defect in thymic tolerance causes T eell-mediated autoimmunity in a murine model of COPA syndrome . J Immunol 2020 ; 204 : 2360 – 73 . Google Scholar Crossref Search ADS PubMed WorldCat Author notes Aaqib Zaffar Banday and Anit Kaur contributed equally to the manuscript. © The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
TI - Splice-site mutation in COPA gene and familial arthritis – a new frontier
JF - Rheumatology
DO - 10.1093/rheumatology/keaa354
DA - 2021-01-05
UR - https://www.deepdyve.com/lp/oxford-university-press/splice-site-mutation-in-copa-gene-and-familial-arthritis-a-new-kISE855k5x
SP - e7
EP - e9
VL - 60
IS - 1
DP - DeepDyve
ER -