Type I Interferonopathy due to a Homozygous Loss-of-Inhibitory Function Mutation in STAT2.

Autor: Zhu G; MRC Human Genetics Unit, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK., Badonyi M; MRC Human Genetics Unit, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK., Franklin L; Cytokine Signalling Unit, Institut Pasteur, Paris, France., Seabra L; Institut Imagine, Paris, France., Rice GI; Division of Evolution, Infection and Genomics, The University of Manchester, Manchester, UK., Anne-Boland-Auge; Centre National de Recherche en Génomique Humaine (CNRGH), Université Paris-Saclay, CEA, Evry, France., Deleuze JF; Centre National de Recherche en Génomique Humaine (CNRGH), Université Paris-Saclay, CEA, Evry, France., El-Chehadeh S; Institut de Génétique Médicale d'Alsace, Strasbourg, France., Anheim M; Service de Neurologie, Centre de Référence Des Maladies Neurogénétiques Rares, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.; Fédération de Médecine Translationnelle de Médecine de Strasbourg, Strasbourg, France.; Institut de Génétique Et de Biologie Moléculaire Et Cellulaire, UMR7104, INSERM-U964/CNRS, Université de Strasbourg, Illkirch, France., de Saint-Martin A; Unité de Neurologie Pédiatrique, Centre de Référence Des Epilepsies Rares, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.; UMR 7104 INSERM U1258, IGBMC-CNRS, Strasbourg, France., Pellegrini S; Cytokine Signalling Unit, Institut Pasteur, Paris, France., Marsh JA; MRC Human Genetics Unit, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK., Crow YJ; MRC Human Genetics Unit, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK. yanickcrow@mac.com.; Institut Imagine, Paris, France. yanickcrow@mac.com., El-Daher MT; MRC Human Genetics Unit, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK.
Jazyk: angličtina
Zdroj: Journal of clinical immunology [J Clin Immunol] 2023 May; Vol. 43 (4), pp. 808-818. Date of Electronic Publication: 2023 Feb 08.
DOI: 10.1007/s10875-023-01445-3
Abstrakt: Purpose: STAT2 is both an effector and negative regulator of type I interferon (IFN-I) signalling. We describe the characterization of a novel homozygous missense STAT2 substitution in a patient with a type I interferonopathy.
Methods: Whole-genome sequencing (WGS) was used to identify the genetic basis of disease in a patient with features of enhanced IFN-I signalling. After stable lentiviral reconstitution of STAT2-null human fibrosarcoma U6A cells with STAT2 wild type or p.(A219V), we performed quantitative polymerase chain reaction, western blotting, immunofluorescence, and co-immunoprecipitation to functionally characterize the p.(A219V) variant.
Results: WGS identified a rare homozygous single nucleotide transition in STAT2 (c.656C > T), resulting in a p.(A219V) substitution, in a patient displaying developmental delay, intracranial calcification, and up-regulation of interferon-stimulated gene (ISG) expression in blood. In vitro studies revealed that the STAT2 p.(A219V) variant retained the ability to transduce an IFN-I stimulus. Notably, STAT2 p.(A219V) failed to support receptor desensitization, resulting in sustained STAT2 phosphorylation and ISG up-regulation. Mechanistically, STAT2 p.(A219V) showed defective binding to ubiquitin specific protease 18 (USP18), providing a possible explanation for the chronic IFN-I pathway activation seen in the patient.
Conclusion: Our data indicate an impaired negative regulatory role of STAT2 p.(A219V) in IFN-I signalling and that mutations in STAT2 resulting in a type I interferonopathy state are not limited to the previously reported R148 residue. Indeed, structural modelling highlights at least 3 further residues critical to mediating a STAT2-USP18 interaction, in which mutations might be expected to result in defective negative feedback regulation of IFN-I signalling.
(© 2023. The Author(s).)
Databáze: MEDLINE
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