Molecular genetic studies on Behcet's disease

白塞病的分子遗传学研究

• 批准号: 08457466
• 负责人: OHNO Shigeaki
• 金额: $ 4.74万
• 依托单位: Yokohama City University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08457466/
• 关键词: Behcet's desease; Molecular genetics; HLA-BィイD1*ィエD15101; MICA; MICB; Disease susceptibility gene; HLA-B*5101; HLA; YACクローン

In order to investigate the molecular genetic mechanism of Behcet's disease, we studied the HLA-B region which is located on the short arm of chromosome 6 (6p21.3). A YAC clone, Y109, was isolated from the YAC library using HLA class I specific primers. We investigated the new genes around the HLA-B which are in linkage disequilibrium with HLA-BィイD1*ィエD15101.Y109 was found to span 600kb. This region was confirmed to contain NOB1, NOB2, NOB3, MICA and MICB, which are non-HLA genes. Investigation of MICB polymorphism by PCR-SSP showed no significant association with Behcet's disease. In contrast, the frequency of MICA-A6 was significantly higher in the patients than in the normal controls.Furthermore, investigation of amino acids in the peptide binding region of MICA-A6 (exon 3) showed that they were all valine at position 122.Studies on the other gene regions near the telomere on 6p showed weak association with Behcet's disease, and it was concluded that the responsible gene for Behcet's disease is located in the 230 kb between HLA-C and MICB.Further studies on the association of Behcet's disease with these new genes are indicated. Establishment of transgenic animals of HLA-BィイD1*ィエD15101-MICA-A6 are now in progress in our laboratory, to elucidate the exact molecular genetic mechanism of this difficult disease.

为了探讨白塞病的分子遗传学机制，我们对位于6号染色体短臂（6p21.3）的HLA-B区域进行了研究。使用HLA I类特异性引物从YAC文库中分离YAC克隆Y109。我们对HLA-B基因组中与HLA-B连锁不平衡的新基因Y109进行了研究，发现Y109的长度为600 kb。该区域被证实含有NOB 1、NOB 2、NOB 3、云母和MICB，它们是非HLA基因。PCR-SSP检测MICB基因多态性与白塞病无明显相关性。而MICA-A6基因在白塞病患者中的频率明显高于正常人，其第3外显子肽结合区的氨基酸序列分析表明，第122位氨基酸均为缬氨酸，而6p端粒附近的其他基因序列分析表明，其与白塞病的相关性较弱。提示白塞病的致病基因位于HLA-C和MICB之间的230 kb区域，这些新基因的发现为白塞病的进一步研究提供了依据。本实验室正在建立HLA-B转基因动物，以阐明这一疑难疾病的确切分子遗传学机制。

项目成果

Mizuki N.: "A strong association between HLA-BィイD1*ィエD15101 and Behcet's disease in Greek Patients"Tissue Antigens. 50. 57-60 (1997)

Mizuki N.：“希腊患者中 HLA-B1*D15101 与白塞氏病之间的密切关联”组织抗原 50. 57-60 (1997)。

Mizuki N.,et al: "Immunogenetic studies of Behcet's disease" Rev Rhum Engl Ed. 63. 520-527 (1996)

Mizuki N. 等人：“白塞氏病的免疫遗传学研究”Rev Rhum Engl Ed。

Mizuki N.,et al: "Isolation of cDNA and genomic clones of a human Ras-related GTP-binding protein gene and its chromosomal localization to the long arm of chromosome 7,7q36" Genomics. 34. 114-118 (1996)

Mizuki N. 等人：“人类 Ras 相关 GTP 结合蛋白基因的 cDNA 和基因组克隆的分离及其对染色体 7,7q36 长臂的染色体定位”基因组学。

Mizuki N.,et al: "Pathogenic gene responsible for the predisposition to Behcet's disease" Intern Rev Immunol. 14. 33-48 (1997)

Mizuki N. 等人：“导致白塞氏病易感性的致病基因”Intern Rev Immunol。

Ando H.: "Identification of a novel HLA-B allele(B^*4202)in a Saudi Arabian family with Behcet's disease." Tissue Antigens. 49. 526-528 (1997)

Ando H.：“在患有白塞氏病的沙特阿拉伯家族中鉴定出一种新的 HLA-B 等位基因 (B^*4202)。”