Analysis of mutations and recombination activity in RAG-deficient patients

• Published in: Clinical immunology (Orlando, Fla.) Fla.), 2011-02, Vol.138 (2), p.172-177
• Main Authors: Asai, Erika, Wada, Taizo, Sakakibara, Yasuhisa, Toga, Akiko, Toma, Tomoko, Shimizu, Takashi, Nampoothiri, Sheela, Imai, Kohsuke, Nonoyama, Shigeaki, Morio, Tomohiro, Muramatsu, Hideki, Kamachi, Yoshiro, Ohara, Osamu, Yachie, Akihiro
• Format: Article
• Language: English
• Subjects: Allergy and Immunology; Autoimmunity; Autoimmunity - genetics; B-Lymphocytes - immunology; Biological and medical sciences; Child, Preschool; Cytomegalovirus; Cytomegalovirus Infections - genetics; DNA Mutational Analysis; DNA-Binding Proteins - genetics; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Homeodomain Proteins - genetics; Humans; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunopathology; Infant; Infant, Newborn; Infection; Lymphocytes T; Male; Medical sciences; Missense mutation; Mutation; Nuclear Proteins - genetics; Omenn syndrome; RAG deficiency; RAG1 protein; RAG2 protein; SCID; Severe combined immunodeficiency; Severe Combined Immunodeficiency - genetics; T-cell receptor; TCRγδ + T cells; V(D)J recombination
• ISSN: 1521-6616; 1521-7035
• DOI: 10.1016/j.clim.2010.11.005

Abstract Mutations in the recombination activating genes ( RAG1 or RAG2 ) can lead to a variety of immunodeficiencies. Herein, we report 5 cases of RAG deficiency from 5 families: 3 of Omenn syndrome, 1 of severe combined immunodeficiency, and 1 of combined immunodeficiency with oligoclonal TCRγδ+ T cells, autoimmunity and cytomegalovirus infection. The genetic defects were heterogeneous and included 6 novel RAG mutations. All missense mutations except for Met443Ile in RAG2 were located in active core regions of RAG1 or RAG2 . V(D)J recombination activity of each mutant was variable, ranging from half of the wild type activity to none, however, a significant decrease in average recombination activity was demonstrated in each patient. The reduced recombination activity of Met443Ile in RAG2 may suggest a crucial role of the non-core region of RAG2 in V(D)J recombination. These findings suggest that functional evaluation together with molecular analysis contributes to our broader understanding of RAG deficiency.