Analysis of mutations and recombination activity in RAG-deficient patients.
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.
Department of Pediatrics, School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.
Erika
E
Asai
Taizo
T
Wada
Yasuhisa
Y
Sakakibara
Akiko
A
Toga
Tomoko
T
Toma
Takashi
T
Shimizu
Sheela
S
Nampoothiri
Kohsuke
K
Imai
Shigeaki
S
Nonoyama
Tomohiro
T
Morio
Hideki
H
Muramatsu
Yoshiro
Y
Kamachi
Osamu
O
Ohara
Akihiro
A
Yachie
D015551:Autoimmunity / Q000235:genetics; D001402:B-Lymphocytes / Q000276:immunology; D002675:Child, Preschool; D003586:Cytomegalovirus Infections / Q000235:genetics; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D016511:Severe Combined Immunodeficiency / Q000235:genetics*
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; C499311:RAG2 protein, human; C064658:RAG-1 protein