RAG1 Deficiency May Present Clinically as Selective IgA Deficiency

• Published in: Journal of clinical immunology Vol. 35; no. 3; pp. 280 - 288
• Main Authors: Kato, Tamaki, Crestani, Elena, Kamae, Chikako, Honma, Kenichi, Yokosuka, Tomoko, Ikegawa, Takeshi, Nishida, Naonori, Kanegane, Hirokazu, Wada, Taizo, Yachie, Akihiro, Ohara, Osamu, Morio, Tomohiro, Notarangelo, Luigi D., Imai, Kohsuke, Nonoyama, Shigeaki
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.04.2015; Springer Nature B.V
• Subjects: Biomedical and Life Sciences; Biomedicine; Child, Preschool; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; IgA Deficiency - blood; IgA Deficiency - genetics; IgA Deficiency - immunology; Immunology; Infectious Diseases; Internal Medicine; Male; Medical Microbiology; Mutation; Original Research; Polymorphism, Single Nucleotide; Receptors, Antigen, T-Cell - metabolism; V(D)J Recombination; primary immunodeficiency; TRECs; KRECs; IgA deficiency; deficiency; V(D)J recombination
• ISSN: 0271-9142; 1573-2592
• DOI: 10.1007/s10875-015-0146-4

Background Recombination-activating gene (RAG) 1 and 2 deficiency is seen in patients with severe combined immunodeficiency (SCID) and Omenn syndrome. However, the spectrum of the disease has recently expanded to include a milder phenotype. Objective We analyzed a 4-year-old boy who was initially given the diagnosis of selective immunoglobulin A deficiency (SIgAD) based on immunoglobulin serum levels without any opportunistic infections, rashes, hepatosplenomegaly, autoimmunity or granulomas. The patient was found to be infected with varicella zoster; however, the clinical course was not serious. He produced antiviral antibodies. Methods We performed lymphocyte phenotyping, quantification of T cell receptor excision circles (TRECs) and kappa deleting recombination excision circles (KRECs), an analysis of target sequences of RAG1 and 2, a whole-genome SNP array, an in vitro V(D)J recombination assay, a spectratype analysis of the CDR3 region and a flow cytometric analysis of the bone marrow. Results Lymphocyte phenotyping demonstrated that the ratio of CD4+ to CD8+ T cells was inverted and the majority of CD4+T cells expressed CD45RO antigens in addition to the almost complete lack of B cells. Furthermore, both TRECs and KRECs were absent. Targeted DNA sequencing and SNP array revealed that the patient carried a deletion of RAG1 and RAG2 genes on the paternally-derived chromosome 11, and two maternally-derived novel RAG1 missense mutations (E455K, R764H). In vitro analysis of recombination activity showed that both RAG1 mutant proteins had low, but residual function. Conclusions The current case further expands the phenotypic spectrum of mild presentations of RAG deficiency, and suggests that TRECs and KRECs are useful markers for detecting hidden severe, as well as mild, cases.