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

Darier病（DD）和Hailey-Hailey病（HHD）是近年来发现的两种常染色体显性遗传性皮肤病，其致病基因已被确定。这两个基因编码的分子属于钙ATP酶，将钙从胞浆中螯合到内质网或高尔基体。DD基因以ATP 2A 2表示，HHD基因以ATP 2C 1表示。(1)在HHD患者中发现了超过40个ATP 2C 1突变，从而证实HHD是由ATP 2C 1突变引起的。(2)在正常人皮肤外植体的器官培养中，加入肌浆网钙ATP酶2型亚型（DD基因产物）抑制剂或ATP 2A 2的反义寡核苷酸可诱导类似DD的组织学变化。由于ATP 2A 2半基因敲除小鼠没有表现出任何与DD相似的特异性皮肤变化，因此到目前为止，该器官培养系统似乎只是DD的实验模型。(3)UVB（50 ml/cm ~ 2）照射培养的正常人角质形成细胞后，ATP_（2A）2和ATP_（2C）1的表达受到自发性抑制。(4)细胞外钙离子浓度从低（0.03mM）到高（1.8mM）的增加自发地刺激培养的正常人角质形成细胞中ATP 2A 2和ATP 2C 1的表达。(5)在培养的正常人角质形成细胞中，向培养基中添加IL-6下调了这两种基因的表达。

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.