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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
  • Aysima Hacisuleyman,
  • Ahmet Gul,
  • Burak Erman
Aysima Hacisuleyman
Universite de Lausanne Departement de biologie computationnelle

Corresponding Author:[email protected]

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Ahmet Gul
Istanbul Universitesi Dahili Tip Bilimleri
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Burak Erman
Koc Universitesi Kimya ve Biyoloji Muhendisligi Bolumu
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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.
13 Aug 2024Submitted to PROTEINS: Structure, Function, and Bioinformatics
16 Aug 2024Submission Checks Completed
16 Aug 2024Assigned to Editor
16 Aug 2024Review(s) Completed, Editorial Evaluation Pending
30 Aug 2024Reviewer(s) Assigned
25 Oct 2024Editorial Decision: Revise Major