RAG genomic variation causes autoimmune diseases through specific structure-based mechanisms of enzyme dysregulation. iScience 2023 Oct 20;26(10):108040
Date
10/19/2023Pubmed ID
37854700Pubmed Central ID
PMC10579426DOI
10.1016/j.isci.2023.108040Scopus ID
2-s2.0-85174692439 (requires institutional sign-in at Scopus site)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 RAG activity changes. We applied our model to 711 additional RAG variants observed in population studies and identified a subset that may impair RAG function. Thus, we demonstrated a fundamental advance in the mechanistic interpretation of human genetic variations spanning from rare and undiagnosed diseases to population health.
Author List
Haque N, Kawai T, Ratnasinghe BD, Wagenknecht JB, Urrutia R, Notarangelo LD, Zimmermann MTAuthors
Neshatul Haque Postdoctoral Fellow in the Mellowes Center for Genomic Sciences and Precision Medicine department at Medical College of WisconsinJessica B. Wagenknecht Bioinformatics Analyst I in the Mellowes Center for Genomic Sciences and Precision Medicine department at Medical College of Wisconsin
Michael T. Zimmermann PhD Director, Assistant Professor in the Clinical and Translational Science Institute department at Medical College of Wisconsin
