Oligoclonal expansion of T lymphocytes with multiple second-site mutations leads to Omenn syndrome in a patient with RAG1-deficient severe combined immunodeficiency.
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.
Wada
Taizo
T
Department of Pediatrics, Graduate School of Medical Science, Kanazawa University, 13-1 Takaramachi, Kanazawa 920-8641, Japan. taizo@ped.m.kanazawa-u.ac.jp
Toma
Tomoko
T
Okamoto
Hiroyuki
H
Kasahara
Yoshihito
Y
Koizumi
Shoichi
S
Agematsu
Kazunaga
K
Kimura
Hirokazu
H
Shimada
Akira
A
Hayashi
Yasuhide
Y
Kato
Masahiko
M
Yachie
Akihiro
A
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
D018398:Homeodomain Proteins; C064658:RAG-1 protein