Heterozygous mutations in the C-terminal domain of COPA underlie a complex autoinflammatory syndrome
Selket Delafontaine, … , Jérôme Delon, Isabelle Meyts
Selket Delafontaine, … , Jérôme Delon, Isabelle Meyts
Published January 4, 2024
Citation Information: J Clin Invest. 2024;134(4):e163604. https://doi.org/10.1172/JCI163604.
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Research Article Immunology

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

Abstract

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 COPAR1142X and COPAR1058C 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.

Authors

Selket Delafontaine, Alberto Iannuzzo, Tarin M. Bigley, Bram Mylemans, Ruchit Rana, Pieter Baatsen, Maria Cecilia Poli, Daisy Rymen, Katrien Jansen, Djalila Mekahli, Ingele Casteels, Catherine Cassiman, Philippe Demaerel, Alice Lepelley, Marie-Louise Frémond, Rik Schrijvers, Xavier Bossuyt, Katlijn Vints, Wim Huybrechts, Rachida Tacine, Karen Willekens, Anniek Corveleyn, Bram Boeckx, Marco Baggio, Lisa Ehlers, Sebastian Munck, Diether Lambrechts, Arnout Voet, Leen Moens, Giorgia Bucciol, Megan A. Cooper, Carla M. Davis, Jérôme Delon, Isabelle Meyts

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Figure 1

Three heterozygous mutations in the CTD of COPA in 6 patients with an autoinflammatory and autoimmune phenotype.

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Three heterozygous mutations in the CTD of COPA in 6 patients with an au...
(A) Pedigrees of families A, B, and C with indication of the genotype, assigned with the amino acid changes, below each individual. Affected individuals are indicated by black filled symbols and an arrow, gray half-filled symbols indicate unaffected heterozygous carriers, and open shapes indicate unaffected family members. Squares designate males and circles females. Patient 2 (B.II.1) died at the age of 7 due to hemophagocytic lymphohistiocytosis and multiple organ failure. Patients 5 (C.II.3) and 6 (C.II.4) are dizygotic twins. Sanger sequencing chromatograms for COPA, performed on genomic DNA, are shown, covering a 15 bp snapshot around the mutation. Red arrows indicate the position of the mutation. (B) Medical imaging for patient 1 (A.II.3). Brain MRI (T2-weighted images) shows a hyperintense optic chiasm (red arrow), indicative of neuromyelitis optica with involvement of the optic chiasm (top left panel). Spinal cord MRI (T2 weighted images) illustrates a swollen spinal cord with central hyperintensity (red bracket), ranging from the level of cervical vertebra 4 (C4) to thoracic vertebra 8 (T8), revealing transverse myelitis (bottom left panel). Chest computed tomography (CT) demonstrates bronchiectasis (top right panel), and MRI of the abdomen depicts hepatosplenomegaly (bottom right panel, red arrows). (C) Chest CT of patient 2 (B.II.1) shows signs of an alveolar hemorrhage and centrilobular nodules.