Studies on roles of malformation of the cornified cell envelope in phathogenesis of severe ichthyoses

大多数非大疱性常染色体隐性遗传性鱼鳞病分为两个不同的主要临床实体：板层状鱼鳞病和非大疱性先天性鱼鳞状红皮病。这两种类型的常染色体隐性遗传性鱼鳞病的典型临床特征有很大不同。然而，也有一些病例表现出介于板层状鱼鳞病和非大疱性先天性鱼鳞状红皮病之间的中间表型。角化细胞包膜相关蛋白已被认为是这些鱼鳞病的候选分子。转谷氨酰胺酶1是一种约92kD的膜相关转谷氨酰胺酶，是三种转谷氨酰胺酶的主要亚型，在表皮中表达。表皮中的转谷氨酰胺酶被认为至少部分负责角化的细胞膜前体蛋白的组装，形成角化的细胞膜。在本研究中，在超微结构和免疫组织化学上，半数以上的日本板层状鱼鳞病和少数非大疱性先天性鱼鳞状红皮病的病例发现角化细胞被膜异常。免疫电子显微镜证实这些病例角化细胞被膜畸形。用TGM1直接测序的突变分析表明，大多数板层状鱼鳞病和角化细胞膜缺陷的非大疱性先天性鱼鳞状红皮病患者存在TGM1突变，导致表皮转谷氨酰胺酶1活性降低。从我们的数据中已经发现了TGM1基因突变的几种水平的基因型/表型相关性。另一方面，在日本的板层状鱼鳞病和非大疱性先天性鱼鳞状红皮病患者中，TGM1基因突变的患者与转谷氨酰胺酶正常的患者在临床表现上没有明显的差异。

Most cases of non-bullous autosomal recessive ichthyoses are divided into two distinct major clinical entities, lamellar ichthyosis and non-bullous congenital ichthyosiform erythroderma. Typical clinical features of these two types of autosomal recessive ichthyoses are quite different. However, there are cases showing an intermediate phenotype between lamellar ichthyosis and non-bullous congenital ichthyosiform erythroderma. Cornified cell envelope-associated proteins have been raised as a candidate molecule for these ichthyosises. Transglutaminase 1, a membrane-associated transglutaminase of about 92 kD, is the major subtype of three transglutaminases expressed in the epidermis. Transglutaminases in the epidermis are thought to be responsible at least in part for the assembly of cornified cell envelope precursor proteins to form cornified cell envelope. In the present study, ultrastructurally and immunohistologically, abnormal cornified cell envelope had been found in more than half of the Japanese cases of lamellar ichthyosis and a small number of the Japanese cases of non-bullous congenital ichthyosiform erythroderma. Malformation of the cornified cell envelope in the cases was confirmed by immunoelectron micryscopy. Mutation analysis by the direct sequencing of TGM1 revealed that the majority of the cases of lamellar ichthyosis and non-bullous congenital ichthyosiform erythroderma with defective cornified cell envelope had TGM1 mutations that resulted in the reduced transglutaminase 1 activity in the epidermis. Several levels of genoetype/phenotype correlation for mutations in the TGM1 gene have been suggested from our data. On the other hand, in ou series of the Japanese patients with lamellar ichthyosis and non-bullous congenital ichthyosiform erythroderma, no clear difference in the clinical pictures was seen between patients with TGM1 mutations and those who had normal transglutaminse activity.