Elucidation of Pathogenetic Mechanisms of Severe Ichthyoses and Establishment of New Method for the Diagnosis and Prenatal Disease Detection

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Pathogenetic mechanisms of autosomal recessive congenital ichthyosis are still unknown although malformation or the cornified cell envelope arising from mutations of the transglutaminase (Tgase) 1 gene is reported to be the cause of sine cases of lamellar ichthyosis. In this study, using immunofluorescence, immunoelectron microscopic and molecular genetic techniques, pathogenetic mechanisms of several types of autosomal recessive severe ichthyosis were investigated in many affected Japanese families. Immunofluorescent and immunoelectron microscopic observations revealed that abnormality in expression and distribution of several proteins associated with cornified cell envelope formation in the epidermal keratinocytes. Heteroduplex analysis and direct sequencing or the PCR-amplified genes were performed to the putative responsible genes for the ichthyosis phenotypes from results of the morphologic observations. The mutations found were confirmed by restriction enzyme cutting and allele specific oligonucleotide hybfidization methods. In some families, precise and definite diagnosis can be made on the basis of the information of responsible genes. In addition, the results of this study contributed to the establishment of methodology of early prenatal diagnosis of the severe congenital ichthyoses.