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 Pyrin
protein mutations by using mutual information (MI) as a measure to
quantify the correlation between residue motions or fluctuations and
associated changes affecting the phenotype. The concept of MI profile
shift is presented to quantify changes in MI upon mutation, revealing
insights into residue-residue interactions at critical positions. We
apply this method to the 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 MI
shifts, for the pyrin example the negative shifts, as indicators of
severe functional 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 the pathogenesis of FMF and offers a
framework for identifying potential therapeutic targets based on MI
profile changes induced by mutations.