A dominant pathogenic MEFV mutation causes atypical pyrin-associated periodic syndromes

Area of Science:

• Genetics
• Immunology
• Molecular Biology

Background:

• Pyrin protein, encoded by the MEFV gene, is crucial for innate immunity.
• It senses Rho GTPase modifications and activates the pyrin inflammasome.
• Dysregulation of pyrin inflammasome is implicated in autoinflammatory diseases.

Purpose of the Study:

• To identify and characterize a novel MEFV gene variant.
• To investigate the mechanism of pyrin inflammasome activation by this variant.
• To understand the clinical phenotype associated with the novel variant.

Main Methods:

• Genetic sequencing to identify the MEFV p.E583A variant.
• Analysis of patient peripheral blood mononuclear cells (PBMCs) and cell lines.
• Pyrin inflammasome assembly and activation assays.
• Truncation experiments to elucidate the variant's effect on pyrin structure.

Main Results:

• A novel, de novo MEFV p.E583A dominant variant was identified in three family members.
• Patients presented with recurrent chest and abdominal pain, differing from classical MEFV mutations.
• The E583A variant induced pyrin inflammasome assembly and activation in patient cells.
• Colchicine treatment effectively managed the patients' phenotype.
• Mechanistic studies showed the variant disrupts pyrin's autoinhibitory structure.

Conclusions:

• The MEFV p.E583A variant causes a distinct autoinflammatory phenotype.
• This variant activates the pyrin inflammasome by affecting pyrin's autoinhibition.
• The findings provide new insights into pyrin inflammasome regulation and autoinflammatory disease mechanisms.