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A systematic analysis of recombination activity and genotype-phenotype correlation in human recombination-activating gene 1 deficiency

Lookup NU author(s): Professor Andrew GenneryORCiD

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Abstract

Background: The recombination-activating gene (RAG) 1/2 proteins play a critical role in the development of T and B cells by initiating the VDJ recombination process that leads to generation of a broad T-cell receptor (TCR) and B-cell receptor repertoire. Pathogenic mutations in the RAG1/2 genes result in various forms of primary immunodeficiency, ranging from T 2 B 2 severe combined immune deficiency to delayed-onset disease with granuloma formation, autoimmunity, or both. It is not clear what contributes to such heterogeneity of phenotypes. Objective: We sought to investigate the molecular basis for phenotypic diversity presented in patients with various RAG1 mutations. Methods: We have developed a flow cytometry-based assay that allows analysis of RAG recombination activity based on green fluorescent protein expression and have assessed the induction of the Ighc locus rearrangements in mouse Rag1(-/-) pro-B cells reconstituted with wild-type or mutant human RAG1 (hRAG1) using deep sequencing technology. Results: Here we demonstrate correlation between defective recombination activity of hRAG1 mutant proteins and severity of the clinical and immunologic phenotype and provide insights on the molecular mechanisms accounting for such phenotypic diversity. Conclusions: Using a sensitive assay to measure the RAG1 activity level of 79 mutations in a physiologic setting, we demonstrate correlation between recombination activity of RAG1 mutants and the severity of clinical presentation and show that RAG1 mutants can induce specific abnormalities of the VDJ recombination process.

Publication metadata

Author(s): Lee YN, Frugoni F, Dobbs K, Walter JE, Giliani S, Gennery AR, Al-Herz W, Haddad E, LeDeist F, Bleesing JH, Lauren AH, Pai SY, Nelson RP, El-Ghoneimy DH, El-Feky RA, Reda SM, Hossny E, Soler-Palacin P, Fuleihan RL, Patel NC, Massaad MJ, Geha RS, Puck JM, Palma P, Cancrini C, Chen K, Vihinen M, Alt FW, Notarangelo LD

Publication type: Article

Publication status: Published

Journal: Journal of Allergy and Clinical Immunology

Year: 2014

Volume: 133

Issue: 4

Pages: 1099-1108.e12

Print publication date: 01/04/2014

ISSN (print): 0091-6749

ISSN (electronic): 1097-6825

Publisher: Mosby, Inc.

URL: http://dx.doi.org/10.1016/j.jaci.2013.10.007

DOI: 10.1016/j.jaci.2013.10.007

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