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Functional analysis of Darier disease gene and Hailey-Hailey disease gene

Darier病基因和Hailey-Hailey病基因的功能分析

基本信息

批准号：
12670837
负责人：
IKEDA Shigaku
金额：
$ 1.54万
依托单位：
Juntendo University, School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670837/
关键词：
Darier disease Hailey-Hailey disease ATP2A2 ATP2C1 gene expression quantitative RT-PCR UVB cytokines organ culture keratinocytes

项目摘要

Darier disease (DD)and Hailey-Hailey disease (HHD)are autosomal dominantily inherited skin diseases recently whose causative genes are identified. Both of genes encode the molecules belong to calcium ATPase that sequesters calcium from cytosole to ER or Golgi. DD gene is symbolized as ATP2A2 and HHD gene is symbolized as ATP2C1.In this study, below mentioned facts were identified in 2000 to 2001. (1) More than 40 mutations in ATP2C1 were identified in the patients with HHD, thus it is confirmed that HHD is caused by mutations in ATP2C1. (2) Histopathological changes similar to DD was induced by the addition of inhibitor of sarco-endoplasmic reticulum calcium ATPase type 2 isoform (DD gene product) or antisense oligonucleotides to ATP2A2 in organ culture of normal human skin explants. Because ATP2A2 hemi-knock out mice did not show any specific skin changes similar to that of DD, so far this organ culture system seems to be only an experimental model for DD. (3) Expression of ATP2A2 and ATP2C1 was spontaneously suppressed by irradiation of UVB (50ml/cm2) in cultured normal human keratinocyted. (4) Increase in extracellular calcium concentration form low (0.03mM) to high (1.8mM) spontaneously stimulated the expression of ATP2A2 and ATP2C1 in cultured normal human keratinocytes. (5) Addition of IL-6 to the culture media down-regulated the expression of both genes in cultured normal human keratinocytes.

达里尔病（DD）和黑利-黑利病（HHD）是近年来发现的常染色体显性遗传性皮肤病。这两个基因编码的分子都属于钙三磷酸腺苷酶，它将钙从细胞质分离到内质网或高尔基体。DD基因符号为ATP2A2， HHD基因符号为ATP2C1。在这项研究中，以下提到的事实是在2000年至2001年确定的。(1)在HHD患者中发现了40多个ATP2C1突变，从而证实HHD是由ATP2C1突变引起的。(2)将肌内质网钙atp酶2型异构体抑制剂（DD基因产物）或反义寡核苷酸添加到正常人皮肤组织培养的ATP2A2中，可引起与DD相似的组织病理变化。由于ATP2A2半敲除小鼠未表现出与DD类似的特异性皮肤变化，因此目前该器官培养系统似乎只是DD的实验模型。(3)在培养的正常人角化细胞中，UVB （50ml/cm2）照射可自发抑制ATP2A2和ATP2C1的表达。(4)细胞外钙浓度由低（0.03mM）升高到高（1.8mM），自发刺激培养的正常人角质形成细胞中ATP2A2和ATP2C1的表达。(5)在培养的正常人角质形成细胞中，在培养基中添加IL-6可下调这两个基因的表达。