Browsing by Author "Jansen, Katrien"

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    Heterozygous mutations in the C-terminal domain of COPA underlie a complex autoinflammatory syndrome
    (2024) Delafontaine, Selket; Iannuzzo, Alberto; Bigley, Tarin; Mylemans, Bram; Rana, Ruchit; Baatsen, Pieter; Poli Harlowe, María Cecilia; Rymen, Daisy; Jansen, Katrien; Mekahli, Djalila; Casteels, Ingele; Cassiman, Catherine; Demaerel, Philippe; Lepelley. Alice; Frémond, Marie; Schrijvers, Rik; Bossuyt, Xavier; Vints, Katlijn; Huybrechts, Wim; Tacine, Rachida; Willekens, Karen; Corveleyn, Anniek; Boeckx, Bram; Baggio, Marco; Ehlers, Lisa; Munck, Sebastian; Lambrechts, Diether; Voet, Arnout; Moens, Leen; Bucciol, Giorgia; Cooper, Megan; Davis, Carla; Delon, Jérôme; Meyts, Isabelle
    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.
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    Structural mapping of GABRB3 variants reveals genotype-phenotype correlations
    (2021) Johannesen, Katrine; Iqba, Sumaiya; Guazz, Milena; Mohammadi, Nazanin; Pérez, Eduardo; Schaefer, Elise; De Saint Martin, Anne; Abiwarde, Marie; McTague, Amy; Pons, Roser; Piton, Amelie; Kurian, Manju; Ambegaonkar, Gautam; Firth, Helen; Sanchis, Alba; Deprez, Marie; Jansen, Katrien; De Waele, Liesbeth; Briltra, Eva; Verbeek, Nienke; Van Kempen, Marjan; Fazeli, Walid; Striano, Pasquale; Zara, Federico; Visser, Gerhard; Braakman, Hilde; Haeusle, Martin; Elbracht, Miriam; Vahe, Ulvi; Smol, Thomas; Lemke, Johannes; Platzer, Konrad; Kennedy, Joanna; Martin, Karl; Ping, Billie; Smyth, Kimberly; Kaplan, Julie; Thomas, Morgan; Dewenter, Malin; Dinopoulos, Argirios; Campbell, Arthur; Lal, Dennis; Lederer, Damien; Liao, Vivian; Ahring, Philip; Møller, Rikke; Gardella, Elena
    Purpose: Pathogenic variants in GABRB3 have been associated with a spectrum of phenotypes from severe developmental disorders and epileptic encephalopathies to milder epilepsy syndromes and mild intellectual disability (ID). In this study, we analyzed a large cohort of individuals with GABRB3 variants to deepen the phenotypic understanding and investigate genotype-phenotype correlations. Methods: Through an international collaboration, we analyzed electro-clinical data of unpublished individuals with variants in GABRB3, and we reviewed previously published cases. All missense variants were mapped onto the 3-dimensional structure of the GABRB3 subunit, and clinical phenotypes associated with the different key structural domains were investigated. Results: We characterized 71 individuals with GABRB3 variants, including 22 novel subjects, expressing a wide spectrum of phenotypes. Interestingly, phenotypes correlated with structural locations of the variants. Generalized epilepsy, with a median age at onset of 12 months, and mild-to-moderate ID were associated with variants in the extracellular domain. Focal epilepsy with earlier onset (median: age 4 months) and severe ID were associated with variants in both the pore-lining helical transmembrane domain and the extracellular domain. Conclusion: These genotype-phenotype correlations will aid the genetic counseling and treatment of individuals affected by GABRB3-related disorders. Future studies may reveal whether functional differences underlie the phenotypic differences.

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