Xeroderma pigmentosum : a disease model for clinical, cellular and molecular consequences of ultraviolet radiation-induced damage

• Main Author: Sethi, Mieran Kaur
• Format: Dissertation
• Language: English
• Published: King's College London 2017

XP is considered a disease of failed repair of direct UVR-induced DNA photoproducts, leading to severe sunburn, extremely high rates of skin cancer, and death in young adulthood from complications relating to malignancy and neurodegeneration. Most experiments in the literature on XP cells, both for diagnosis and interpretation of photobiological processes, have used non-solar UVC radiation. Discernable differences in clinical phenotype have emerged from long-term follow-up of XP patients in the UK National XP clinic. The development of a sunburn severity score revealed that XP-C, XP-E and XP-V patients have normal sunburn reactions; a cohort of milder XP-A patients has been identified, arising from a likely founder mutation yielding less than 5% read-through of normal XPA protein. Deep phenotyping, including the development of ocular and neurological severity scores, has resulted in precise correlation of XP phenotype with the causal mutation, enabling the development of personalized prognostic advice for XP patients worldwide. Based on XP phenotype patterns, molecular experiments were conducted on skin fibroblasts from a range of XP complementation groups using environmentally relevant 385nm UVA-1 compared with 254nm UVC. UVA-1 was a more effective inducer of MMP mRNA and protein than UVC, by a mechanism independent of CPD. MMP upregulation was proportional with ROS generation, and this effect was attenuated when vitamin E was added to cell culture, providing indirect evidence that UVA-1-induced ROS was the main cause of MMP upregulation. The effects of UVA in XP literature have been largely ignored; studies here highlight that XP is a disease of impaired defenses against direct and indirect UVR-induced damage, which may explain sunburn, photoageing, skin cancer and neurological phenotype. These studies demonstrate the importance of translational research in this rare genetic disease. Photoprotection from solar-UVA, together with antioxidants, may provide a future gold standard for photoageing in the general population.