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

Yu Nee Lee, Francesco Frugoni, Kerry Dobbs, Jolan E. Walter, Silvia Giliani, Andrew R. Gennery, Waleed Al-Herz, Elie Haddad, Francoise Ledeist, Jack H. Bleesing, Lauren A. Henderson, Sung Yun Pai, Robert P. Nelson, Dalia H. El-Ghoneimy, Reem A. El-Feky, Shereen M. Reda, Elham Hossny, Pere Soler-Palacin, Ramsay L. Fuleihan, Niraj C. PatelMichel J. Massaad, Raif S. Geha, Jennifer M. Puck, Paolo Palma, Caterina Cancrini, Karin Chen, Mauno Vihinen, Frederick W. Alt*, Luigi D. Notarangelo

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

124 Scopus citations


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-B - 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.

Original languageEnglish (US)
Pages (from-to)1099-1108.e12
JournalJournal of Allergy and Clinical Immunology
Issue number4
StatePublished - Apr 2014


  • Omenn syndrome
  • Recombination-activating gene 1
  • V(D)J recombination
  • autoimmunity
  • genotype-phenotype correlation
  • immune repertoire
  • severe combined immune deficiency

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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