173 A Model to Unravel Pathways Underpinning Palmoplantar Homeostasis and Disease

Tylosis with oesophageal cancer (TOC) is a rare syndrome associated focal non-epidermolytic palmoplantar keratoderma (NEPPK), high, lifetime risk of developing squamous cell carcinoma (OSCC), and gain-of-function mutations in RHBDF2 (encoding iRhom2). To date, there lack useful representative model to study the development NEPPK OSCC vivo, which might aid our understanding hyperproliferative skin disease predisposition. CRISPR-Cas9 was used generate novel mouse TOC that contains heterozygous Rhbdf2I156T/+ mutation mirrors UK family mutation, RHBDF2I186T/+. Mice were comprehensively phenotyped bulk spatial RNA-sequencing performed on forepaw skin. First observations found mice developed thickened, reddened footpads around ∼8 months age, paw epidermis significantly thicker than wildtype comparisons. This matched human condition, presents late restricted weight-bearing areas. Bulk RNA-Sequencing identified an upregulation keratin genes, Krt14, Krt16, Krt17; alarmins, S100a8 S100a9; AP-1 transcription factor subunit, Fos. Pathway analysis revealed TNF-α signalling enriched skin, directly linked iRhom2, regulates sheddase, ADAM17. Spatial reveal exact location these transcriptomic events, gene expression vary considerably between footpad sole regions. Moreover, Fos upregulated sole, mirrored data, highlights possible role for development. We introduce new, clinically syndrome, TOC. present lesions, analyses have several genes be key drivers NEPPK. Further, this may enhance biology.