An attempt to analyze the pathogenesis of congenital keratinization disorders, and the future prospects of gene therapy for the patients in our out-patient department

Congenital keratinization disorders are classified according to clinical, histopathological and genetic findings. Keratin is a form of cytoskeleton consisting of intermediate filaments in epidermal cells. Mutations in genes encoding several types of keratin have been implicated in the pathogenesis of “keratin diseases”. Previous studies have shown that these genodermatoses are due to mutations in the KRT1, 10 and KRT2E genes. We have reported on the molecular analyses of several patients with rare autosomal dominant disorders, namely, bullous congenital ichthyosiform erythroderma (BCIE) and ichthyosis bullosa Siemens. Future studies will also evaluate the relationship between genotype and phenotype in these disorders. The cornified cell envelope (CCE), a form of membrane-skeleton in terminally differentiating keratinocytes, consists of precursor proteins such as involucrin and loricrin, catalyzed by transglutaminase. As in keratin disorders, recent studies have identified the genetic mutations responsible for “CCE diseases”. Lamellar ichthyosis and Vohwinkel disease, caused by mutations in the TGM1 and LOR genes, respectively, are two examples of such genodermatoses. Discoveries such as those given above have improved diagnostic capabilities and genetic counseling, allowing researchers to focus on the molecular mechanisms involved in the pathogenesis of these diseases. Moreover, identification of the pathogenic genes has led to the generation of mouse models for some of the disorders, further facilitating research into the pathological mechanisms. A study of the keratin 10 deficient mouse, a model for BCIE, and the preparation of a mouse model for Vohwinkel disease, both recently performed by Pr. D Roop's Lab. are reviewed in this article. Given these developments, gene therapy has become an increasingly attractive mode of treating congenital keratinization disorders. This review focuses on ex vivo approaches for gene therapy. In addition, we discuss the advantages of employing transgenic mouse model systems to test the efficacy of a given gene therapy prior to the clinical trials.