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）布卢姆综合征和共济失调性脑静脉曲张是常染色体隐性人体疾病，其特征是免疫缺陷，基因组不稳定性和发展癌症的易感性。最近的数据表明，这两个基因BLM和ATM的产物在识别异常DNA结构时相互作用并起作用。为了研究这两个分子在DNA损伤中的功能，我们在DT4O鸡B-淋巴细胞细胞系中产生了ATM - / - BLM - / - 的双重敲除。双突变细胞可行，并表现出ATM - / - 和BLM - / - 细胞的各种特征。结果表明，ATM和BLM在识别DNA中不同形式的损害方面具有很大不同的作用，但也与部分重叠的功能相吻合，在识别辐射受损的DNA中休息时的部分重叠功能。2）超级IGM免疫缺陷是一种免疫障碍，其特征是正常或升高的血清IgM水平和降低的血清IgG和IGA级别的升高，以及降低了血清IgG级别，该水平降低了，而无需降低了IGA的水平，而无需降低了IGA的水平。细胞。激活诱导的胞苷脱氨酶（AID）是高IGM综合征常染色体隐性形式的致病基因（HIGM2）。我们确定了一个点突变，导致患者辅助基因（R190X）外显子5中的终止密码子。在患者中未检测到辅助基因的其他突变。她的家人的其他成员未发现同样的突变。假定辅助基因的突变为主要负面形式。

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。

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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)

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。

Watanabe M et al.: "Predominant expression of 950delCAG of IL-18R alpha chain cDNA is associated with reduced IFN-gamma production"J. Allergy Clin. Immnnol.. 109. 669-675 (2002)

Watanabe M 等人：“IL-18R α 链 cDNA 950delCAG 的主要表达与 IFN-γ 产生减少有关”J.