Role of Mutual Information Profile Shifts in Assessing the Pathogenicity of Mutations on Protein Functions: The Case of Pyrin Variants Associated with Familial Mediterranean Fever

Abstract

This paper presents a novel method to assess the pathogenicity of mutations by affecting a phenotype and/or its severity, with a specific emphasis on the role of mutual information (MI) as a measure to quantify the correlation between residue motions or fluctuations. The concept of MI profile shift is presented to quantify changes in MI upon mutation, revealing insights into residue-residue interactions. We apply this method to the case of Pyrin protein variants, which are associated with an autosomal recessively inherited disease called familial Mediterranean fever (FMF), since the available tools do not help predict the pathogenicity of the most penetrant variants. We demonstrate the utility of MI profile shifts in assessing the effects of mutations on protein stability, function, and disease phenotype. The importance of negative MI shifts as indicators of severe effects is emphasized, along with exploring potential compensatory mechanisms indicated by positive MI shifts, which are otherwise random and inconsequential. The paper also discusses challenges in relating MI profile changes to disease severity and advocates for comprehensive analysis considering genetic, environmental, and stochastic factors. Overall, this study provides insights into the molecular mechanisms underlying disease progression and offers a framework for identifying potential therapeutic targets based on MI profile changes induced by mutations.