Recombination activity of human recombination-activating gene 2 (RAG2) mutations and correlation with clinical phenotype

The Journal of Allergy and Clinical Immunology
Irit TiroshYu Nee Lee

Abstract

Mutations in recombination-activating gene (RAG) 1 and RAG2 are associated with a broad range of clinical and immunologic phenotypes in human subjects. Using a flow cytometry-based assay, we aimed to measure the recombinase activity of naturally occurring RAG2 mutant proteins and to correlate our results with the severity of the clinical and immunologic phenotype. Abelson virus-transformed Rag2-/- pro-B cells engineered to contain an inverted green fluorescent protein (GFP) cassette flanked by recombination signal sequences were transduced with retroviruses encoding either wild-type or 41 naturally occurring RAG2 variants. Bicistronic vectors were used to introduce compound heterozygous RAG2 variants. The percentage of GFP-expressing cells was evaluated by using flow cytometry, and high-throughput sequencing was used to analyze rearrangements at the endogenous immunoglobulin heavy chain (Igh) locus. The RAG2 variants showed a wide range of recombination activity. Mutations associated with severe combined immunodeficiency and Omenn syndrome had significantly lower activity than those detected in patients with less severe clinical presentations. Four variants (P253R, F386L, N474S, and M502V) previously thought to be pathogenic we...Continue Reading

Citations

Oct 12, 2018·Clinical and Experimental Immunology·S S MeshaalA M Elmarsafy
Feb 1, 2019·Pediatric Allergy and Immunology : Official Publication of the European Society of Pediatric Allergy and Immunology·Hagen Ott
Sep 20, 2019·Expert Review of Clinical Immunology·Adeeb A BulkhiJolan E Walter
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Oct 25, 2021·The Journal of Allergy and Clinical Immunology·Neha SethJavier Chinen

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