In silico modeling guides identification of novel JAK1 variants associated with immune dysregulation
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.
Authors
- Yohann Schmitt (ORCID: https://orcid.org/0000-0001-7267-9225)
- Marie‐Claude Stolzenberg (ORCID: https://orcid.org/0000-0001-8026-0360)
- Fabienne Mazerolles (ORCID: https://orcid.org/0000-0002-5991-614X)
- Jonathan Ciron (ORCID: https://orcid.org/0000-0002-3386-6308)
- Marianna Parlato (ORCID: https://orcid.org/0000-0002-8750-082X)
- Bénédicte Neven (ORCID: https://orcid.org/0000-0001-8941-0935)
- Camille Brunaud
- Quentin Riller (ORCID: https://orcid.org/0000-0003-3323-0235)
- Matías Oleastro
- Silvia Danielian
- Jérôme Hadjadj (ORCID: https://orcid.org/0000-0002-2520-3272)
- Marie Jeanpierre (ORCID: https://orcid.org/0009-0009-2758-6180)
- Charlotte Boussard (ORCID: https://orcid.org/0000-0002-1237-8321)
- Cédric Léonard
- João Farela Neves (ORCID: https://orcid.org/0000-0003-4740-6094)
- Aude Magérus (ORCID: https://orcid.org/0000-0001-7365-699X)
- María Martha Katsicas (ORCID: https://orcid.org/0000-0002-3898-7555)
- Cécile Masson (ORCID: https://orcid.org/0000-0001-7870-7821)
- Angélique Vinit (ORCID: https://orcid.org/0000-0003-3344-4911)
- Bénédicte Hoareau‐Coudert (ORCID: https://orcid.org/0000-0002-6575-7085)
- Estibaliz Lazaro (ORCID: https://orcid.org/0000-0002-4206-7399)
- Mariana Villa
- Pierre Quartier (ORCID: https://orcid.org/0000-0002-1769-549X)
- Judith Yancoski
- Frédéric Rieux‐Laucat (ORCID: https://orcid.org/0000-0001-7858-7866)
- Hervé Isambert (ORCID: https://orcid.org/0000-0001-9638-8545)
- Orianne Debeaupuis (ORCID: https://orcid.org/0000-0002-1393-3980)
- Olivier Pellé (ORCID: https://orcid.org/0000-0002-0163-6487)
- Giselle Villarreal (ORCID: https://orcid.org/0009-0003-5502-1917)
- Jean‐Louis Stephan
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Université Paris Cité (FR)
- Université Paris Sciences et Lettres (FR)
- Garrahan Hospital (AR)
- Sorbonne Université (FR)
- Sorbonne Paris Cité (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Hôpital Saint-Antoine (FR)
- Nova Medical (United States) (US)
- Hôpital Nord (FR)
- Hospital de Dona Estefânia (PT)
- Hôpital Cardiologique du Haut-Lévêque (FR)
- Hôpital Purpan (FR)
- Centre Hospitalier Universitaire de Saint-Étienne (FR)
- Center for Rheumatology (US)
- Institut des Maladies Génétiques Imagine (FR)
- Universidade Nova de Lisboa (PT)
Publication Details
- Journal
- EMBO Molecular Medicine
- Published
- 2025-10-24
- DOI
- https://doi.org/10.1038/s44321-025-00317-0
- Citations
- 1
- Primary Topic
- Cytokine Signaling Pathways and Interactions
- Type
- article
- Field-Weighted Citation Impact
- 1.05