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Background The B30.2 variants lead to most relevant severity forms of familial Mediterranean fever (FMF) manifestations. The B30.2 domain plays a key role in protein-protein interaction (PPI) of pyrin with other apoptosis proteins and in regulation the cascade of inflammatory reactions. Pyrin-casp1 interaction is mainly responsible for the dysregulation of the inflammatory responses in FMF. Lower binding affinity was observed between the mutant B30.2 pyrin and casp1 without the release of the complete pathogenicity mechanism. The aim of this study was to identify the possible effects of the interface pocked residues in B30.2/SPRY-Casp1/p20 complex using molecular mechanics simulation and in silico analysis. Results It was found that Lys671Met, Ser703Ile, and Ala744Ser variants led mainly to shift of the binding affinity (∆G), dissociation constant (Kd), and root mean square deviation (RMSD) in B30.2/SPRY-Casp1/p20 complex leading to dynamic disequilibrium of the p20-B30.2/SPRY complex toward its complex form. The current pathogenicity model and its predicted implementation in the relevant colchicine dosage were delineated. Conclusion The molecular mechanics analysis of B30.2/SPRY-p20 complex harboring Lys671Met, Ser703Ile, and Ala744Ser variants showed dynamic disequilibrium of B30.2/SPRY-casp1/p20complex in context of the studied variants that could be a new computational model for FMF pathogenicity. This study also highlighted the specific biochemical markers that could be useful to adjust the colchicine dose in FMF patients.

Throughout the last 20 years, the concept of auto-inflammation is developed, culminating with the finding of how gene mutations of Mediterranean Fever (MEFV) seemed to be causally linked to Familial Mediterranean fever (FMF). The autoinflammatory illnesses presently constitute a wide variety of disorders that have mutual signs of frequent fever, the incidence of hyper-reactive immune cells of hereditary origin, and indicators of inflammation that may occur systemically or specific to an organ with no autoimmunity specific infection. The key causes of the unregulated inflammation are the myeloid innate immune cells which mainly induced production of excessive inflammatory cytokines as IL-1β and IL-18. Deficiencies through various signalling mechanisms regulating innate immune response, especially a single and even multiple inflammasomes hyperreactivity, remain the essence of pathological autoinflammatory phenotype. While FMF would be a monogenic autoinflammatory syndrome, it is genetically complicated and affected by environmental influences. Lately, epigenetic dysregulation has appeared to be a further cause of pathogenesis.Throughout this survey, we are addressing the epigenetic involvement pathways within (FMF).

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