title: Oligoclonal expansion of T lymphocytes with multiple second-site mutations leads to Omenn syndrome in a patient with RAG1-deficient severe combined immunodeficiency.
abstract: Omenn syndrome (OS) is a rare primary immunodeficiency characterized by the presence of activated/oligoclonal T cells, eosinophilia, and the absence of circulating B cells. OS patients carry leaky mutations of recombination activating genes (RAG1 or RAG2) resulting in partial V(D)J recombination activity, whereas null mutations cause severe combined immunodeficiency with absence of mature T and B cells (T-B- SCID). Here we describe somatic mosaicism due to multiple second-site mutations in a patient with RAG1 deficiency. We found that he is homozygous for a single base deletion in the RAG1 gene, which results in frameshift and likely abrogates the protein function. However, the patient showed typical OS features. Molecular analysis revealed that several second-site mutations, all of which restored the RAG1 reading frame and resulted in missense mutations, were demonstrated in his T cells. These findings suggest that his revertant T-cell mosaicism is responsible for OS phenotype switched from T-B- SCID.
authors.affiliation: Department of Pediatrics, Graduate School of Medical Science, Kanazawa University, 13-1 Takaramachi, Kanazawa 920-8641, Japan. taizo@ped.m.kanazawa-u.ac.jp
authors.forename: Taizo
authors.initials: T
authors.lastname: Wada
authors.forename: Tomoko
authors.initials: T
authors.lastname: Toma
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Okamoto
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Kasahara
authors.forename: Shoichi
authors.initials: S
authors.lastname: Koizumi
authors.forename: Kazunaga
authors.initials: K
authors.lastname: Agematsu
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Kimura
authors.forename: Akira
authors.initials: A
authors.lastname: Shimada
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Masahiko
authors.initials: M
authors.lastname: Kato
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yachie
mesh_terms: D049109:Cell Proliferation; D004802:Eosinophilia; D016368:Frameshift Mutation; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007223:Infant; D008213:Lymphocyte Activation; D008297:Male; D009154:Mutation; D020125:Mutation, Missense; D016511:Severe Combined Immunodeficiency / Q000235:genetics*; D013577:Syndrome; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; C064658:RAG-1 protein