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Functional Assessment of Disease-Associated Pyrin Variants
Daria Chirita1,2, Yvan Jamilloux1,2,3, Thomas Henry4,5
1CIRI (Centre International de Recherche en Infectiologie), Univ Lyon, Inserm U1111, Lyon, France.
Abstract:
The pyrin inflammasome detects effectors and toxins that inhibit RhoA GTPases and triggers inflammatory cytokines release and a fast cell death termed pyroptosis. Ancient plague pandemics in the Mediterranean basin have selected in the human population pyrin variants that can trigger an autoinflammatory disease termed familial Mediterranean fever (FMF). In addition, distinct mutations in MEFV, the gene encoding pyrin, cause a different rare autoinflammatory disease termed pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND). As of today, more than 385 MEFV variants have been described although for most of them, whether they are pathogenic variant or benign polymorphism is unknown.Here, we describe different methods using primary human monocytes or engineered monocytic cell lines to functionally characterize MEFV variants, determine their potential pathogenicity, and classify them as either FMF-like or PAAND-like variants.
Insights
Researchers developed methods to test MEFV gene variants, which cause autoinflammatory diseases like familial Mediterranean fever (FMF) and pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND). This helps classify unknown variants and understand their disease association.
Area of Science:
- Immunology
- Genetics
- Molecular Biology
Background:
- The pyrin inflammasome mediates inflammatory responses and pyroptosis upon detecting RhoA GTPase inhibitors.
- Human populations have selected for pyrin variants linked to autoinflammatory diseases, including familial Mediterranean fever (FMF) and pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND).
- Over 385 variants in the MEFV gene, which encodes pyrin, are known, but their pathogenicity remains largely uncharacterized.
Purpose of the Study:
- To develop and describe functional assays for characterizing MEFV variants.
- To determine the pathogenicity of unknown MEFV variants.
- To classify MEFV variants as FMF-like or PAAND-like.
Main Methods:
- Utilizing primary human monocytes for functional characterization.
- Employing engineered monocytic cell lines for variant analysis.
- Developing assays to assess inflammasome activation and downstream effects.
Main Results:
- Established methods for functional characterization of MEFV variants in relevant cellular models.
- Demonstrated the ability to assess pathogenicity and disease-specific classification (FMF-like vs. PAAND-like) of MEFV variants.
- Provided a framework for understanding the functional consequences of genetic variations in pyrin.
Conclusions:
- Functional characterization assays are crucial for understanding the pathogenicity of MEFV variants.
- These methods enable the classification of variants, aiding in the diagnosis and management of autoinflammatory diseases.
- This work contributes to a deeper understanding of pyrin inflammasome function and its role in human disease.
