THE MOLECULAR ANALYSIS OF THE PRIMARY IMMUNODEFICIENCY ASSOCIATED WITH HIGH PREDISPOSITION TO CANCER

与高癌症易感​​性相关的原发性免疫缺陷的分子分析

• 批准号: 14570738
• 负责人: KANEKO Hideo
• 金额: $ 2.24万
• 依托单位: GIFU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570738/
• 关键词: Bloom syndrome; BLM; Ataxia-telangiectasia; double knockout; radiation sensitivity; Hyper IgM type II; dominant negative; activation induced cytidine deaminase; Ataxia-telanigectasia; ATM; 会合; hyper IgM症候群; dominat negative AID; ダブルノックアウト

1)Bloom syndrome and ataxia-telangiectasia are autosomal recessive human disorders characterized by immunodeficiency, genome instability and predisposition to develop cancer. Recent data reveal that the products of these two genes, BLM and ATM, interact and function together in recognizing abnormal DNA structures. To investigate the function of these two molecules in DNA damage, recognition, we generated double knockouts of ATM-/-BLM-/-in the DT4O chicken B-lymphocyte cell line. The double mutant cells were viable and exhibited a variety of characteristics of both ATM-/-and BLM-/-cells. The results suggest that ATM and BLM have largely distinct roles in recognizing different forms of damage in DNA, but also compatible with partially overlapping functions in recognizing breaks in radiation-damaged DNA.2)Hyper-IgM immunodeficiency is an immunological disorder characterized by normal or elevated serum IgM levels, and reduced serum IgG and IgA levels, due to the disruption of immunoglobulin-class switching in B cells. Activation-induced cytidine deaminase (AID) is the causative gene for the autosomal recessive form of hyper-IgM syndrome (HIGM2). We identified a point mutation leading to 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 mutation of the AID gene is assumed to be of the dominant negative form.

1)Bloom综合征和共济失调毛细血管扩张症是常染色体隐性遗传病，其特征是免疫缺陷、基因组不稳定和易患癌症。最近的数据显示，这两个基因的产物，BLM和ATM，在识别异常DNA结构中相互作用并共同起作用。为了研究这两种分子在DNA损伤识别中的功能，我们在鸡b淋巴细胞系dt40中产生了ATM-/- blm -/的双敲除。双突变细胞存活，并表现出ATM-/和BLM-/细胞的多种特征。结果表明，ATM和BLM在识别不同形式的DNA损伤方面有很大不同的作用，但在识别辐射损伤DNA断裂方面也有部分重叠的功能。2)超IgM免疫缺陷是一种免疫疾病，其特征是血清IgM水平正常或升高，血清IgG和IgA水平降低，这是由于B细胞中免疫球蛋白类转换的中断。激活诱导胞苷脱氨酶（AID）是常染色体隐性型高igm综合征（HIGM2）的致病基因。我们在患者的AID基因（R190X）外显子5中发现了一个导致停止密码子的点突变。在患者中未检测到AID基因的其他突变。在她家族的其他成员中没有发现同样的突变。艾滋病基因的突变被认为是显性阴性形式。

项目成果

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Sakaguchi H.等人：“牛奶过敏中人白细胞抗原-肽-T细胞受体复合物之间的相互作用”Clin。

Matui, E., Kaneko, H.et al.: "Current advances in pediatric asthma and other allergic diseases. Edited by Morikawa A"JOMO NEWSPAPER Co., Ltd.. 37-42 (2002)

Matui，E.，Kaneko，H.等：“小儿哮喘和其他过敏性疾病的最新进展。森川A编辑”JOMO NEWSPAPER Co., Ltd. 37-42 (2002)

Fukao T, kaneko H, et al.: "Disruption of the BLM gene in ATM null DT40 cells does not exacerbate either phenotype."Oncogene. (in press).

Fukao T、kaneko H 等人：“ATM 无效 DT40 细胞中 BLM 基因的破坏不会加剧任何一种表型。”癌基因。

Beamish H, et al.: "Functional link between BLM defective in Bloom's syndrome and the ataxia-telangiectasia mutated protein, ATM."J Biol Chem. 277. 30515-30523 (2002)

Beamish H 等人：“布卢姆综合征中 BLM 缺陷与共济失调毛细血管扩张突变蛋白 ATM 之间的功能联系。”J Biol Chem。

Teramoto T, Kaneko H, et al.: "Progressive multifocal leukoencephalopathy in a patient with XLA."Scand.J.Infect.Dis.. 35. 909-910 (2003)

Teramoto T、Kaneko H 等人：“XLA 患者的进行性多灶性白质脑病。”Scand.J.Infect.Dis.. 35. 909-910 (2003)