In silico modeling guides identification of novel JAK1 variants associated with immune dysregulation

ABSTRACT: Characterization of primary immune dysregulations and deficiencies disorders caused by hyper-activating 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 PIDD led to the identification of five novel variants located in key cis-regulatory and catalytic domains, with predicted GOF activity. Ectopic expression of these variants in cell l

SUBMITTER: Marie Jeanpierre 

PROVIDER: S-SCDT-10_1038-S44321-025-00317-0 | biostudies-other |

REPOSITORIES: biostudies-other