Genetics and Pathobiology of Cutaneous Mosaic Disorders

PROJECT SUMMARY: Cutaneous mosaic disorders are severe, rare genetic skin disorders appearing in patterns due to somatic mutation during embryonic development. The timing of mutation determines the identity and extent of affected tissue and the risk of systemic disease. We have found that consequences of such mutations can be severe as in rapidly-growing, treatment-unresponsive congenital hemangiomas due to GNA14 mutation, or severe osteomalacia in the cutaneous- skeletal hypophosphatemia syndrome due to multi-lineage somatic activating RAS mutations. A broad collaborative network of physicians and scientists have enabled our work to gain new insight into skin biology through genetic discoveries in cutaneous mosaic disorders. In the last funding period, we identified three new genes for cutaneous mosaic disorders, provided evidence for phenotypic expansion in six others, and proved efficacy of a novel pathogenesis- directed therapy for porokeratosis now commonly used in dermatology care. We now propose a more comprehensive and rigorous approach to cutaneous mosaic disorders we have found less frequently have mutations in known genes and represent a greater opportunity for discovery. These include mosaic inflammatory disorders which are localized, severe manifestations of common inflammatory disorders such as atopic dermatitis and psoriasis, hamartomatous mosaic disorders, vascular anomalies, and atypical presentations of epidermal nevi. We screen for mutations in potential causative genes, and employ an integrated multiomics approach to discover novel genetic causes and gain biological insight into disease pathogenesis. We will utilize patient-derived cells and tissue to interrogate the function of novel genes, and will employ organotypic tissue to study and prove pathogenesis of identified mutations. For a limited number of compelling, novel genes previously unrecognized to be relevant to skin biology, we will employ CRISPR-generated mouse models to study disease pathobiology. These studies will continue to identify molecular pathways central to the complex processes of epidermal differentiation, self-renewal, and inflammation, and will provide critical context for future biologic studies and development of novel therapeutics.