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

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 activit

SUBMITTER: Jeanpierre M 

PROVIDER: S-EPMC12686074 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature