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鱼鳞病分为两种不同的主要临床实体，板层性鱼鳞病和非大疱性先天性鱼鳞样红皮病。这两种常染色体隐性鱼鳞病的典型临床特征有很大的不同。然而，也有病例表现出介于板层状鱼鳞病和非大疱性先天性鱼鳞样红皮病之间的中间表型。角化细胞包膜相关蛋白已被提出作为这些鱼鳞病的候选分子。谷氨酰胺转氨酶1是一种约92 kD的膜相关谷氨酰胺转氨酶，是表皮表达的三种谷氨酰胺转氨酶的主要亚型。表皮中的转谷氨酰胺酶被认为至少部分地负责角化细胞包膜前体蛋白的组装以形成角化细胞包膜。在本研究中，半数以上的日本板层状鱼鳞病患者和少数日本非大疱性先天性鱼鳞样红皮病患者在超微结构和免疫组织学上发现了异常的角化细胞包膜。经免疫电镜检查，证实角膜包膜有畸形。TGM1直接测序的突变分析显示，大多数板层状鱼鳞病和非大疱性先天性鱼鳞样红皮病伴角质化细胞包膜缺陷的病例都存在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提出了TGM1基因突变的几个水平的基因型/表型相关性。另一方面，在我们的日本板层状鱼鳞病和非大泡性先天性鱼鳞样红皮病系列患者中，TGM1突变患者的临床表现与谷氨酰胺转氨酶活性正常的患者无明显差异。

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.