Localisation of a gene for Darier's disease.
Localisation of a gene for Darier's disease.
复制标题
达里尔病基因的定位。
DOI：
10.1093/hmg/2.11.1937
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发表时间：
1993
影响因子：
3.5
通讯作者：
T. Strachan
中科院分区：
文献类型：
--
作者：
R. Bashir;C. Munro;S. Mason;A. Stephenson;J. Rees;T. Strachan
Darier病（毛囊角化病; MEM 124200）是一种常染色体显性遗传疾病，主要影响表皮和附件结构（1-3）。它在世界范围内分布，英国的患病率约为1：50，000。主要病变是丘疹性角化病，通常发生在头部和上躯干。它们首先出现在成年早期，有时在晒伤后出现，并且经常变得广泛和汇合。继发感染是常见的，产生皮肤刺激和令人痛苦的恶臭。该疾病还引起特征性指甲营养不良、掌跖凹陷和角化病，以及口腔、胃肠道和唾液管中的病变。口服维甲酸衍生物对控制皮疹部分有效。对大基因遗传方式的研究表明，成年人完全遗传（2）。然而，新突变的发生率似乎很高;在一个大型系列中，三分之一的病例报告为没有家族病史[1]。在不同的家族中观察到表型的变异性;在一些家族中，主要的病变是扁平疣样角化病。各种研究也描述了相关的精神障碍和癫痫的证据（1-4）。Darier病的病理生理学尚不清楚。超微结构显示，病变角质形成细胞的桥粒数量减少，在角化不良细胞中，张力原丝不直接指向细胞膜，而是聚集在核周环中（5，6）。在免疫细胞化学研究中，病变周围皮肤中的角蛋白是正常的，但在病变细胞中发现了过度增殖相关的角蛋白（7）。桥粒蛋白仅见于皮损周围皮肤的角质形成细胞膜，弥漫性存在于棘层松解细胞的细胞质中，并伴有局灶性核周蓄积（8）。此外，E-钙粘蛋白的免疫染色粘附连接的主要成分，在棘层松解细胞膜上的强度降低，但表位似乎没有内化（9）。张力丝角蛋白和桥粒蛋白分布的变化可能继发于棘层松解（角质形成细胞之间细胞间接触的破坏）;例如，已经提出表皮细胞解离因子参与发病机制（10）。此外，成功的口服类维生素A治疗可以纠正棘层松解，而不会改变桥粒数量的减少（11）。然而，两者合计，证据表明，Darier病是由于受损的结构，装配或桥粒张力丝复合物的组分的稳定性。
Darier's disease (keratosis follicularis; MEM 124200) is an autosomal dominant disorder which principally affects the epidermis and adnexal structures (1-3). It has a world-wide distribution, with a UK prevalence of about 1: 50,000. The main lesions are papular keratoses, usually on the head and upper trunk. They first appear in early adult life, sometimes following sunburn, and often become widespread and confluent. Secondary infection is common, producing skin irritation and distressing mal-odour. The disease also causes a characteristic nail dystrophy, palmoplantar pits and keratoses, as well as lesions in the mouth, gastrointestinal tract and salivary ducts. Oral retinoic acid derivatives are partially effective in controlling the rash. Studies of the mode of inheritance in large kindreds have shown complete penetrance in adults (2). However, the incidence of new mutation appears to be high; a third of cases in one large series were reported as having no family history of the disease (1). Variability in phenotype has been observed between different families; in some families the predominant lesions are the plane wart-like keratoses. Various studies have also described evidence for associated mental disorder and epilepsy (1—4). The pathophysiology of Darier's disease is unknown. Ultrastructuraily, lesional keratinocytes show reduced numbers of desmosomes, and in the dyskeratotic cells the tonofilaments are not directed towards the cell membrane but lie clumped in perinuclear rings (5, 6). In immunocytochemical studies the keratins are normal in perilesional skin, but hyperproliferation associated keratins are found in lesional cells (7). Desmosomal proteins which are seen only at the keratinocyte membrane in perilesional skin, are diffusely present throughout the cytoplasm of acantholytic cells, with focal perinuclear accumulation (8). In addition, immunostaining for E-cadherin (uvomorulin), a major component of adherens junctions, is reduced in intensity on the membrane of acantholytic cells, but the epitopes do not appear to be internalised (9).The changes seen in the distribution of tonofilament keratins and desmosomal proteins may be secondary to acantholysis (disruption of the intercellular contacts between keratinocytes); it has been suggested, for example, that an epidermal cell dissociating factor is involved in pathogenesis (10). Additionally, successful oral retinoid therapy can correct acantholysis without altering the reduced number of desmosomes (11). Taken together, however, the evidence suggests that Darier's disease is due to impaired structure, assembly or stability of the components of the desmosome-tonofilament complexes.