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

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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.