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An attempt to identify the Darier's disease gene and to clarify its function

尝试鉴定达里尔病基因并阐明其功能

基本信息

批准号：
10670806
负责人：
IKEDA Shigaku
金额：
$ 1.15万
依托单位：
Juntendo University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670806/
关键词：
Darier's disease Hailey-Hailey disease ATP2A2 ATP2C1 gene expression quantitative RT-PCR UVB

项目摘要

From 1994, our purpose has been focused on the identification of the Darier's disease (DD) gene. Unfortunately, at least for us, DD gene was found to be sarco/endoplasmic reticulum Ca ATPase type 2 isoform (gene symbol: ATP2A2) by British group in March, 1999. Subsequently, we searched for a Ca ATPase in a chromosomal lesion which harbors the gene for Hailey-Hailey disease (HHD) which shares in part the clinical and histological features with DD. And very recently, we have found that mutations in ATP2C1, a human homolog of a yeast Golgi Ca ATPase, cause HHD.On the other hand, we examined the site specific, and UV induced modulation of mRNA expression of ATP2A2 in human keratinocytes by recently-innovated highly reliable quantitative RT-PCR system. As the results, the expression levels of ATP2A2 in seborrheic areas of normal human skin, the predilected sites in DD, were lower than those in non-seborrheic areas. We further observed that the expression of the gene in cultured normal keratinocytes was suppressed 1 and 3 hr after ultraviolet B irradiation (30mJ/cmィイD12ィエD1), and recoverd at least 12 hr after irradiation. These observations suggest that seborrheic area, specific low level expressions of ATP2A2 may account for the unique distribution of skin eruptions seen in the patients, and that suppression of the gene expression by environmental factors such as ultraviolet B may involve in the formation of the skin lesions in vivo.

从1994年开始，我们的目标一直集中在Darier病（DD）基因的鉴定上。1999年3月，英国研究小组发现DD基因为肌浆网Ca ATP酶2型（基因符号：ATP 2A 2）。随后，我们在一个染色体病变中寻找了一个Ca ATP酶，该病变携带Hailey-Hailey病（HHD）的基因，HHD与DD有部分临床和组织学特征。近年来，我们发现HHD的发生与ATP 2C 1基因突变有关，而ATP 2A 2基因的突变则是导致HHD发生的重要原因。结果表明，正常人皮肤中，在DD的好发部位，即脂溢性区域，ATP 2A 2的表达水平低于非脂溢性区域。在体外培养的正常角质形成细胞中，经30 mJ/cm ~ 2的紫外线B照射后1和3小时，该基因的表达受到抑制，至少在照射后12小时恢复。这些结果表明，脂溢性区域，特定的低水平表达的ATP 2A 2可能解释了独特的分布在患者中看到的皮疹，和抑制基因表达的环境因素，如紫外线B可能参与了在体内的皮肤病变的形成。