Transgenic mouse model to explore the pathophysiology in epidermolytic ichthyosis

Summary: Abstract Body: Epidermolytic ichthyosis (EI) is a rare genetic skin disorder caused by mutations in the keratin 1 (KRT1) or keratin 10 (KRT10) genes, characterized by severe hyperkeratosis accompanied by erythroderma. Although the genetic basis of EI is well-documented, the mechanisms underlying formation of epidermolytic hyperkeratosis remain poorly understood. We hypothesized that mechanical stress, together with abnormal keratin protein is responsible in the formation of epidermolytic hyperkeratosis, the characteristic feature of EI, and aimed to elucidate its pathophysiological mechanisms. First, we examined two cases of EI with pronounced palmoplantar hyperkeratosis caused by KRT1 mutations (p.Glu180Gly and p.Ile487Thr). Our findings revealed that desmosomal proteins, such as desmoglein 1 and plakoglobin, which are normally localized along the cell membrane, were abnormally distributed within the cytoplasm in KRT1 mutant samples (p.Glu180Gly). Similar abnormalities were observed in cultured keratinocytes expressing the mutant KRT1 (p.Glu180Gly). Secondly, we generated a CRISPR/Cas9-edited transgenic mouse carrying the KRT1 mutation (p.Ile487Thr) to determine whether a single gene mutation could reproduce phenotypes similar to those observed in EI patients. The transgenic mouse exhibited skin erosions and plantar hyperkeratosis, resembling those seen in EI patients. Hematoxylin and Eosin staining of the plantar skin revealed epidermolytic hyperkeratosis, a hallmark feature of EI. Immunohistochemical staining further demonstrated that desmosomal components in the transgenic mouse exhibited localization patterns similar to those observed in EI patients. These findings suggest that the transgenic mouse we created is a valuable model for studying EI pathogenesis and holds significant potential for the development of treatments and drug discovery for this disorder. Shuhei Kobayashi¹, Miho Kimura², Yasumitsu Nagao³, Mayumi Komine⁴ 1. Jichi Ika Daigaku, Shimotsuke, Tochigi Prefecture, Japan. 2. Jichi Ika Daigaku, Shimotsuke, Tochigi Prefecture, Japan. 3. Jichi Ika Daigaku, Shimotsuke, Tochigi Prefecture, Japan. 4. Jichi Ika Daigaku, Shimotsuke, Tochigi Prefecture, Japan. Epidermal Structure and Barrier Function