Jonak Constanze, Metze Dieter, Traupe Heiko, Happle Rudolf, König Arne, Trautinger Franz
Department of Dermatology, Medical University of Vienna, Vienna, Austria.
Hum Pathol. 2005 Jun;36(6):686-93. doi: 10.1016/j.humpath.2005.04.009.
In human skin, the 27-kd heat shock protein (hsp27), a member of the small hsp family, is expressed mainly in the upper epidermal layers. Hsp27 functions as a molecular chaperone and is involved in the regulation of cell growth and differentiation. According to experimental evidence, epidermal hsp27, through its chaperone function, might play a role in the assembly of keratin filaments and the cornified cell envelope. This study was conducted to assess the expression pattern of hsp27 in a panel of different ichthyoses. Twelve hereditary and acquired skin diseases associated with an ichthyotic phenotype and 2 corresponding mouse models were investigated by immunohistochemistry on formalin-fixed paraffin-embedded tissue, using a monoclonal antibody specific for hsp27. In ichthyosis vulgaris, lamellar ichthyosis, Sjögren-Larsson syndrome, Netherton syndrome, and acquired ichthyosiform skin condition, the pattern of hsp27 expression resembles healthy human skin. Hsp27 expression was reduced in bullous ichthyosiform erythroderma and annular epidermolytic ichthyosis, and absent in X-linked recessive ichthyosis (1/3 patients) and congenital hemidysplasia with ichthyosiform nevus and limb defects syndrome (1/1). In X-linked dominant chondrodysplasia, 3 small samples are completely negative and 2 larger samples show a pattern resembling random X inactivation. In the mouse models, tattered and bare patches, representing the murine analogues to X-linked dominant chondrodysplasia and congenital hemidysplasia with ichthyosiform nevus and limb defects syndrome, expression of hsp25 (the murine homologue of hsp27) also showed lyonization, demonstrating a clear-cut link between hsp27 expression and underlying molecular pathology. Our results show that loss of hsp27 is a rare event in human epidermis that is associated with specific genetic defects. Among the cases described here, these defects are either in suprabasal keratins or in enzymes involved in cholesterol biosynthesis. The expression and chaperone function of hsp27 might be modified by low/absent epidermal cholesterol and aberrant substrates (ie, keratins) resulting in protein misfolding, dyskeratosis, and thus contribute to the ichthyotic phenotype.
在人类皮肤中，27-kd热休克蛋白（hsp27）是小热休克蛋白家族的一员，主要在上层表皮层表达。Hsp27作为分子伴侣发挥作用，并参与细胞生长和分化的调节。根据实验证据，表皮hsp27通过其伴侣功能，可能在角蛋白丝组装和角质化细胞包膜形成中发挥作用。本研究旨在评估hsp27在一组不同鱼鳞病中的表达模式。通过对福尔马林固定石蜡包埋组织进行免疫组织化学，使用针对hsp27的单克隆抗体，研究了12种与鱼鳞病表型相关的遗传性和获得性皮肤病以及2种相应的小鼠模型。在寻常型鱼鳞病、板层状鱼鳞病、舍格伦-拉尔松综合征、Netherton综合征和获得性鱼鳞病样皮肤疾病中，hsp27的表达模式与健康人类皮肤相似。在大疱性鱼鳞病样红皮病和环状表皮松解性鱼鳞病中，hsp27表达降低，在X连锁隐性鱼鳞病（1/3患者）和先天性半侧发育不良伴鱼鳞病样痣和肢体缺陷综合征（1/1）中hsp27表达缺失。在X连锁显性软骨发育不良中，3个小样本完全阴性，2个大样本显示出类似于随机X染色体失活的模式。在小鼠模型中，代表与X连锁显性软骨发育不良和先天性半侧发育不良伴鱼鳞病样痣和肢体缺陷综合征类似的鼠类模型的破烂和光秃斑块中，hsp25（hsp27的鼠类同源物）的表达也显示出X染色体随机失活，表明hsp27表达与潜在分子病理学之间存在明确联系。我们的结果表明，hsp27缺失在人类表皮中是罕见事件，与特定遗传缺陷相关。在此处描述的病例中，这些缺陷要么存在于基底上层角蛋白中，要么存在于参与胆固醇生物合成的酶中。hsp27的表达和伴侣功能可能会因表皮胆固醇含量低/缺乏以及异常底物（即角蛋白）而发生改变，导致蛋白质错误折叠、角化异常，从而导致鱼鳞病表型。
