In silico modeling guides identification of novel JAK1 variants associated with immune dysregulation
Year: 2025
Type: article
Abstract: Characterization of primary immune dysregulations and deficiency disorders caused by hyperactivating variants of the JAK/STAT pathway highlighted its crucial role in immune cell development and response. To systematically evaluate pathogenic JAK1 variants, we developed a structure-based predictive framework adapting AlphaFold2, modeling both the active and inactive conformations of JAK1. Dual-state modeling of 21,926 JAK1 variants enabled discrimination between pathogenic and benign variants based on their impact on regulatory conformation. Applying this approach to a large cohort of patients with suspected primary immune dysregulation and deficiency led to the identification of five novel variants located in key cis-regulatory and catalytic domains, with predicted gain of function activity. Ectopic expression of these variants in cell line resulted in varying levels of hyperactivation of JAK1 and multiple STATs at baseline. Furthermore, treatment of two patients with Tofacitinib suppressed JAK1 hyperactivation, normalized plasma cytokine levels and interferon signatures, and significantly improved clinical symptoms. These findings reveal diverse mechanisms of JAK1 gain of function, expanding the clinical spectrum JAK1 GOF, and underscore the importance of precise variant characterization for effective personalized therapy.
Source: EMBO Molecular Medicine
Authors: Marie Jeanpierre, Orianne Debeaupuis, Camille Brunaud, Judith Yancoski, Quentin Riller, Jerome Hadjadj, Marie-Claude Stolzenberg, Giselle Villarreal, Marie Martha Katsicas, Mariana Villa, Joao Farela Neves, Jean-Louis Stephan, Cédric Léonard, Estibaliz Lazaro, Jonathan Ciron, Charlotte Boussard, Fabienne Mazerolles, Aude Magerus, Pelle Olivier, Cecile Masson, Yohann Schmitt, Benedicte Hoareau, Angélique Vinit, Bénédicte Neven, Pierre Quartier, Herve Isambert, Matías Oleastro, Silvia Danielian, Marianna Parlato, Frederic Rieux-Laucat
Institutions: Inserm, Université Paris Cité, Institut des Maladies Génétiques Imagine, Centre National de la Recherche Scientifique, Université Paris Sciences et Lettres, Physique des Cellules et Cancers, Institut Curie, Garrahan Hospital, Sorbonne Université, Assistance Publique – Hôpitaux de Paris, Hôpital Saint-Antoine, Unidade Local de Saúde de São José, Hospital de Dona Estefânia, Comprehensive Health Research Centre, Centre Hospitalier Universitaire de Saint-Étienne, Hôpital Cardiologique du Haut-Lévêque, Centre Hospitalier Universitaire de Toulouse, Hôpital Purpan, Structure fédérative de recherche Necker, Production et analyse de données en sciences de la vie et en santé, Hôpital Necker-Enfants Malades
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $7,990
Awards: Deciphering tolerance breakdown in Immune ThrombocytoPenia (BREAK-TOL), Autoimmune CyTopenIa: genetics and pathophysiological mechaNism in pediatric Evans Syndrome, G1608103114, Lupus multiplex families in the identification of new gene defects with strong phenotypic effects: from gene discovery to gene function, Pathways and moleculaR analysEs to Derive multi-omIC signatures predictive to response to Treatment in JIA, G250961418, Autoimmunity/inflammation Through Rnaseq Analysis at the single Cell level for Therapeutic Innovation
OpenAlex ID: W4415501348