Tavadia S, Authi K S, Hodgins M B, Munro C S
Department of Dermatology, South Glasgow University Hospitals, NHS Trust, UK.
Br J Dermatol. 2004 Aug;151(2):440-5. doi: 10.1111/j.1365-2133.2004.06130.x.
Darier's disease (DD) is caused by mutations in ATP2A2, which encodes the sarco/endoplasmic reticulum calcium ATPase type 2 (SERCA2), a member of a family of calcium pumps important in intracellular calcium signalling. SERCA2 has two isoforms. SERCA2a occurs mainly in cardiac and skeletal muscle, whereas SERCA2b occurs ubiquitously and is coexpressed with the related SERCA type 3 (SERCA3) in many tissues. It is not known why mutations in the widely expressed SERCA2 manifest as a focal skin disease.
To provide insight into the pathogenesis of DD by examining SERCA isoform expression in normal skin and DD skin.
Using immunohistochemistry we studied SERCA2a, SERCA2b and SERCA3 expression in nonlesional and lesional skin from seven patients with DD and normal skin from seven control subjects. We quantified SERCA2a and SERCA2b staining intensity by grey scale analysis of fluorescence intensity.
In normal and DD epidermis both SERCA2a and SERCA2b staining was seen. SERCA2a staining in epidermis was less intense relative to pilar muscle whereas SERCA2b staining in epidermis was of marginally greater intensity than in pilar muscle. SERCA3 was not expressed in normal or DD epidermis, but was found in eccrine glands and blood vessels. No reduction was detected in SERCA2a or SERCA2b staining intensity in DD nonlesional epidermis compared with control epidermis. In within-patient comparisons, SERCA2a and SERCA2b staining in lesional epidermis was less intense than in nonlesional epidermis.
Both SERCA2a and SERCA2b are present in epidermis, although the latter may predominate. The absence of coexpressed SERCA3 in epidermis may explain the localization of DD. Comparable SERCA2 staining intensity in nonlesional DD and control epidermis, even in patients predicted to be haploinsufficient, suggests partial compensation by upregulation of the normal allele. Unknown additional factors may trigger focal lesions by overcoming this compensation. Reduced staining intensity in lesional tissue may be secondary, or may reflect local downregulation of SERCA2 expression predisposing to development of focal lesions.
Darier病（DD）由ATP2A2基因突变引起，该基因编码肌浆网/内质网钙ATP酶2型（SERCA2），它是细胞内钙信号传导中重要的钙泵家族成员之一。SERCA2有两种亚型。SERCA2a主要存在于心肌和骨骼肌中，而SERCA2b广泛分布，并在许多组织中与相关的SERCA3型（SERCA3）共表达。目前尚不清楚广泛表达的SERCA2中的突变为何表现为局限性皮肤病。
通过检测正常皮肤和DD皮肤中SERCA亚型的表达，深入了解DD的发病机制。
我们使用免疫组织化学研究了7例DD患者的非皮损和皮损皮肤以及7例对照受试者的正常皮肤中SERCA2a、SERCA2b和SERCA3的表达。通过对荧光强度进行灰度分析来量化SERCA2a和SERCA2b的染色强度。
在正常和DD表皮中均可见SERCA2a和SERCA2b染色。相对于毛囊肌，表皮中的SERCA2a染色较弱，而表皮中的SERCA2b染色强度略高于毛囊肌。SERCA3在正常或DD表皮中不表达，但在汗腺和血管中存在。与对照表皮相比，DD非皮损表皮中未检测到SERCA2a或SERCA2b染色强度降低。在患者内部比较中，皮损表皮中的SERCA2a和SERCA2b染色比非皮损表皮弱。
SERCA2a和SERCA2b均存在于表皮中，尽管后者可能占主导。表皮中未共表达SERCA3可能解释了DD的定位。即使在预计为单倍体不足的患者中，非皮损DD和对照表皮中SERCA2染色强度相当，提示正常等位基因上调可能存在部分补偿。未知的其他因素可能通过克服这种补偿来引发局灶性病变。皮损组织中染色强度降低可能是继发性的，或者可能反映了SERCA2表达的局部下调，易导致局灶性病变的发生。
