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Hum Mutat ; 34(1): 122-31, 2013 Jan.
Article in English | MEDLINE | ID: mdl-22833538

ABSTRACT

Caspase-1 (Interleukin-1 Converting Enzyme, ICE) is a proinflammatory enzyme that plays pivotal roles in innate immunity and many inflammatory conditions such as periodic fever syndromes and gout. Inflammation is often mediated by enzymatic activation of interleukin (IL)-1ß and IL-18. We detected seven naturally occurring human CASP1 variants with different effects on protein structure, expression, and enzymatic activity. Most mutations destabilized the caspase-1 dimer interface as revealed by crystal structure analysis and homology modeling followed by molecular dynamics simulations. All variants demonstrated decreased or absent enzymatic and IL-1ß releasing activity in vitro, in a cell transfection model, and as low as 25% of normal ex vivo in a whole blood assay of samples taken from subjects with variant CASP1, a subset of whom suffered from unclassified autoinflammation. We conclude that decreased enzymatic activity of caspase-1 is compatible with normal life and does not prevent moderate and severe autoinflammation.


Subject(s)
Caspase 1/genetics , Caspase 1/metabolism , Genetic Variation , Interleukin-1beta/metabolism , Biocatalysis , Caspase 1/chemistry , Cell Line , Crystallography, X-Ray , Cytokines/blood , Cytokines/metabolism , DNA Mutational Analysis , Genetic Predisposition to Disease/genetics , HEK293 Cells , Humans , Inflammation/enzymology , Inflammation/genetics , Models, Molecular , Mutation , Protein Multimerization , Protein Structure, Tertiary
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