Unresolved Issues in Familial Mediterranean Fever: Is p.R202Q MEFV Variant Potentially Pathogenetic in Unleashing...

Area of Science:

• Genetics
• Immunology
• Cell Biology

Background:

• Familial Mediterranean Fever (FMF) is an autoinflammatory disorder caused by MEFV gene mutations.
• Genetic testing for FMF is crucial but interpreting variants like p.R202Q can be challenging.
• Inflammation's impact on genomic stability and neutrophil subsets in FMF is not fully understood.

Purpose of the Study:

• To functionally characterize the p.R202Q MEFV alteration.
• To investigate the effects of inflammation on genomic stability and neutrophil subsets in FMF patients.
• To assess the potential role of the p.R202Q variant in FMF pathophysiology.

Main Methods:

• Analysis of FMF, p.R202Q variant, and FMF-like patient cohorts.
• In vitro monocyte stimulation assays with LPS and a PKN1/2 inhibitor.
• Measurement of pro-inflammatory cytokines (IL-1β, IL-18) via ELISA.
• Leukocyte examination using May-Grünwald-Giemsa staining and assessment of nuclear abnormalities.

Main Results:

• Elevated IL-1β levels were observed in LPS-stimulated p.R202Q patients compared to healthy donors.
• Increased immature and hypersegmented neutrophils were found in p.R202Q patients.
• Higher rates of nuclear abnormalities in leukocytes were noted in both FMF and p.R202Q patients.
• No significant differences in IL-1 and IL-18 levels were found between p.R202Q patients and healthy donors after specific monocyte treatment.

Conclusions:

• The p.R202Q MEFV variant does not appear to impair pyrin function.
• p.R202Q variant carriers exhibit cytological alterations similar to FMF patients.
• These cellular changes may contribute to FMF pathogenesis by modulating inflammation.