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Original Article
 

Dysgammaglobulinemia Associated With Glu349del, a Hypomorphic XIAP Mutation
 

Nishida N1, Yang X1, Takasaki I2, Imai K3, Kato K4, Inoue Y5, Imamura T6, Miyashita R7, Kato F8, Yamaide A9, Mori M10, Saito S11, Hara J12, Adachi Y1, Miyawaki T1,13, Kanegane H1,14

1Department of Pediatrics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
2Department of Pharmacology, Graduate School of Science and Engineering, University of Toyama, Toyama, Japan
3Department of Community Pediatrics, Perinatal and Maternal Medicine, Tokyo Medical and Dental University, Tokyo, Japan
4Division of Pediatric Hematology and Oncology, Ibaraki Children's Hospital, Ibaraki, Japan
5Department of Pediatrics, Graduate School of Medicine, Chiba University, Chiba, Japan
6Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
7Department of Pediatrics, Izumiotsu Municipal Hospital, Izumiotsu, Japan
8Department of Pediatrics, Tokyo Women’s Medical University Medical Center East, Tokyo, Japan
9Department of Allergy and Rheumatology, Chiba Children’s Hospital, Chiba, Japan
10Department of Pediatrics, Yokohama City University Medical Center, Yokohama, Japan
11Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan
12Department of Pediatric Hematology/Oncology, Children’s Medical Center, Osaka City General Hospital, Osaka, Japan
13Toyama City Hospital, Toyama, Japan
14Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan

J Investig Allergol Clin Immunol 2015; Vol. 25(3): 205-213
 

 Abstract


Background: X-linked lymphoproliferative syndrome type 2 is a rare hereditary immunodeficiency caused by mutations in the XIAP gene. This immunodeficiency frequently results in hemophagocytic lymphohistiocytosis, although hypogammaglobulinemia and dysgammaglobulinemia are also common.

Objective: We identified 17 patients from 12 Japanese families with mutations in XIAP. The Glu349del mutation was observed in 3 patients, each from a different family. Interestingly, these patients exhibited dysgammaglobulinemia but not hemophagocytic lymphohistiocytosis. We conducted an immunological study of patients carrying Glu349del and other mutations to elucidate the pathogenic mechanisms of dysgammaglobulinemia in patients with mutations in the XIAP gene.

Patients and Methods: We performed an immunological study of 2 patients carrying the Glu349del mutation and 8 patients with other mutations.

Results: Flow cytometry showed that the percentage of memory B cells in patients with a mutation in XIAP was lower than that observed in the healthy controls. The patients with the Glu349del mutation had a lower percentage of memory B cells than those with other mutations. Ig production was reduced in patients with the Glu349del mutation. Increased susceptibility to apoptosis was observed in the patients with other mutations. Susceptibility to apoptosis was normal in patients with Glu349del. Microarray analysis indicated that expression of Ig-related genes was reduced in patients with the Glu349del mutation and that the pattern was different from that observed in the healthy controls or patients with other mutations in XIAP.

Conclusions: Patients carrying the Glu349del mutation in the XIAP gene may have a clinically and immunologically distinct phenotype from patients with other XIAP mutations. The Glu349del mutation may be associated with dysgammaglobulinemia.

Key words: X-linked lymphoproliferative syndrome. XIAP. Dysgammaglobulinemia. Hypomorphic mutation.