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Analysis of protein misfolding as a pathogenetic mechanism in autoinflammatory diseases

Periodic Report Summary - AIPM (Analysis of protein misfolding as a pathogenetic mechanism in autoinflammatory diseases)

Autoinflammatory diseases (AID) are an emerging group of mainly inherited disorders that lead to an innate immune dysregulation of cytokines. The common features are recurrent episodes of inflammation with fever. Systemic amyloidosis is the primary long-term morbidity, while treatment options are scarce. Thus, AID are associated with chronic disability and a significant impact on the health care system. Current data suggest protein misfolding with loss-of-function as a missense-induced principle in the monogenetic AID tumour necrosis factor receptor-1 associated periodic syndrome (TRAPS), and mevalonate kinase deficiency (MKD). The objective of this project was to systematically elucidate the molecular mechanisms underlying MKD. Following cloning of the wild-type (WT) and mutant target protein mevalonate kinase (MK), successful prokaryotic expression and purification of mutant MK supports the hypothesis of protein misfolding in MKD that will be further evaluated by means of analysis of conformation and stability of the mutant protein. These results will then allow to set the ground for future targeted therapies in MKD.