Hyper-IgM syndrome with putative dominant negative mutation in activation-induced cytidine deaminase
Hyper-IgM syndrome with putative dominant negative mutation in activation-induced cytidine deaminase
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DOI：
10.1016/s0091-6749(03)01860-8
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发表时间：
2003-10-01
影响因子：
14.2
通讯作者：
Kondo, N
中科院分区：
文献类型：
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作者：
Kasahara, Y;Kaneko, H;Kondo, N
背景资料：高IgM免疫缺陷是一种免疫性疾病，其特征是由B细胞中IG类转换的破坏引起的正常或升高的血清IgM水平和降低的血清IgG和伊加水平。目的：分析1例日本女性常染色体隐性遗传性高IgM综合征患者的AID基因突变，探讨AID基因突变与临床表型的关系。AID基因表达为谷胱甘肽S-转移酶融合蛋白。RTPCR进行刺激后，患者的PBMC与佛波醇肉豆蔻酸酯乙酸酯和TGF-β。结果：尽管血清IgG水平显着降低，我们的病人没有表现出任何严重感染的倾向，即使没有IG替代治疗。我们确定了一个点突变，导致终止密码子在第5外显子的艾滋病基因（R190 X）的病人。在患者中未检测到AID基因的其他突变。在她的其他家庭成员中没有发现同样的突变。与谷胱甘肽S-转移酶蛋白融合的突变等位基因在与正常等位基因相同的水平上稳定表达。结论：AID基因突变为显性失活突变。这是第一次报告的显性阴性形式的突变在体内。
Background: Hyper-IgM immunodeficiency is an immunologic disorder characterized by normal or increased serum IgM levels and reduced serum IgG and IgA levels caused by the disruption of Ig class switching in B cells. The gene encoding activation-induced cytidine deaminase (AID) is responsible for the autosomal recessive form of hyper-IgM syndrome.Objective: To investigate the relationship between the AID gene mutation and the clinical phenotype, we analyzed the AID gene in a female Japanese patient with the autosomal recessive form of hyper-IgM syndrome.Methods: Genomic DNA and cDNA were extracted from neutrophils and analyzed by means of PCR. The AID gene was expressed as a glutathione S-transferase fusion protein. RTPCR was performed after stimulation of the patient's PBMCs with phorbol myristate acetate and TGF-beta.Results: Despite significantly low serum IgG levels, our patient had not shown a predisposition to any severe infections, even without Ig replacement therapy. We identified a point mutation resulting in the stop codon in exon 5 of the AID gene (R190X) in the patient. No other mutations of the AID gene were detected in the patient. The same mutation was not detected in other members of her family. The mutant allele fused with the glutathione S-transferase protein was expressed stably at the same level as the normal allele. The AID gene expression in the patient was induced by phorbol myristate acetate and TGF-beta.Conclusion: The mutation of the AID gene is assumed to be of the dominant negative form. This is the first report of a dominant negative form of the mutation in vivo.