RAG genomic variation causes autoimmune diseases through specific structure-based mechanisms of enzyme dysregulation.

ABSTRACT: Interpreting genetic changes observed in individual patients is a critical challenge. The array of immune deficiency syndromes is typically caused by genetic variation unique to individuals. Therefore, new approaches are needed to interpret functional variation and accelerate genomics interpretation. We constructed the first full-length structural model of human RAG recombinase across four functional states of the recombination process. We functionally tested 182 clinically observed RAG missense mutations. These experiments revealed dysfunction due to recombinase dysfunction and altered chromatin interactions. Structural modeling identified mechanical and energetic roles for each mutation. We built regression models for RAG1 (R² = 0.91) and RAG2 (R² = 0.97) to predict

SUBMITTER: Haque N 

PROVIDER: S-EPMC10579426 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature