BACKGROUND Pyrin is a newly recognised intracellular regulator of inflammation, and mutations in MEFV, the gene encoding pyrin, are the cause of familial Mediterranean fever. OBJECTIVE To determine if known mutations of MEFV are associated with rheumatoid arthritis (RA) morbidity or can modify RA severity. METHODS The frequency of the three most common MEFV mutations: M694V, V726A, and E148...

We report a 16-year-old female patient with a severe course of multiple sclerosis and concomitant symptoms suggestive of a hereditary autoinflammatory disease. Genetic analyses revealed that she inherited a TNFRSF1A R92Q mutation from her mother and a pyrin E230K mutation from her father. To our knowledge, this is the first report of a patient with severe childhood multiple sclerosis and mutati...

The NOD-like receptor NLRP1 (NLR family, pyrin domain containing 1) senses the presence of the bacterial cell wall component l-muramyl dipeptide (MDP) inside the cell. We determined the crystal structure of the LRR domain of human NLRP1 in the absence of MDP to a resolution of 1.65Å. The fold of the structure can be assigned to the ribonuclease inhibitor-like class of LRR proteins. We compared ...

Introduction Familial Mediterranean Fever (FMF) is the most common hereditary autoinflammatory syndrome affecting >10,000 people in Israel. FMF is caused by mutations in the MEFV gene, which encodes for the pyrin protein that is part of the inflammation complex that activates IL-1b. Evidence from case reports/series and one controlled study supports IL-1 blockage as a potential treatment for FM...

Interferon-inducible protein 16 (IFI16) is a member of the HIN-200 protein family, containing two HIN domains and one PYRIN domain. IFI16 acts as a sensor of viral and bacterial DNA and is important for innate immune responses. IFI16 binds DNA and binding has been described to be DNA length-dependent, but a preference for supercoiled DNA has also been demonstrated. Here we report a specific pre...

The function of gene body DNA methylation in alternative splicing, and its relation to disease pathogenesis is not fully elucidated. The gene for familial Mediterranean fever (MEFV) encodes the pyrin protein and contains a 998 bp CpG island, covering the second exon, which is differentially methylated in FMF patients compared to healthy controls. Our further observation of increased exon 2-spli...

NLRPs (Nucleotide-binding domain, leucine-rich repeat and pyrin domain containing proteins) are a family of pattern-recognition receptors (PRRs) that sense intracellular microbial components and endogenous stress signals. NLRP10 (also known as PYNOD) is a unique NLRP member characterized by a lack of the putative ligand-binding leucine-rich repeat domain. Recently, human NLRP10 has been shown t...

The death domain superfamily, comprising the death domain, death effector domain, caspase recruitment domain and pyrin domain subfamilies, is one of the largest classes of protein interaction modules, and plays a particularly critical function in the assembly and activation of apoptotic and inflammatory complexes. Members of the death domain superfamily share a common structural feature, the 6-...

Activated danger or pathogen sensors trigger assembly of the inflammasome adaptor ASC into specks, large signaling platforms considered hallmarks of inflammasome activation. Because a lack of in vivo tools has prevented the study of endogenous ASC dynamics, we generated a live ASC reporter through CRISPR/Cas9 tagging of the endogenous gene in zebrafish. We see strong ASC expression in the skin ...

The hereditary periodic fevers are a group of Mendelian disorders characterized by seemingly unprovoked fever and localized inflammation. Recent data indicate that these illnesses represent inborn errors in the regulation of innate immunity. Pyrin, the protein mutated in familial Mediterranean fever, defines an N-terminal domain found in a large family of proteins involved in inflammation and a...