MEFV

Abstract: Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by attacks of fever and serositis. In this paper, we define a minimal co-segregating region of 60 kb containing the FMF gene (MEFV) and identify four different transcript units within this region. One of these transcripts encodes a new protein (marenostrin) related to the ret-finger protein and to butyrophilin. Four conservative missense variations co-segregating with FMF have been found within the MEFV candidate gene in 85% of the carrier chromosomes. These variations, which cluster at the carboxy terminal domain of the protein, were not present in 308 control chromosomes, including 162 validated non-carriers. We therefore propose that the sequence alterations in the marenostrin protein are responsible for the FMF disease.

Abstract: The Pyrin inflammasome detects the presence of a pathogen not through recognition of a microbial molecule but by the activity of a bacterial toxin that modifies host Rho activity. The inflammasome complex, mediated by NOD-like receptor (NLR) proteins or other Pyrin-domain pattern recognition receptors (PRRs), plays a critical role in innate immune defence against various microbial infections. Feng Shao and colleagues show that the Pyrin inflammasome detects the presence of the pathogen Burkholderia cenocepacia not by recognizing a microbial molecule, the mechanism commonly adopted by mammalian PRRs, but by sensing the response of host Rho GTPase to a bacterial toxin. Infection with B. cenocepacia is of clinical importance as it can often be fatal in cystic fibrosis and chronic granulomatous disease, therefore the findings reported here could be of relevance to vaccine development and immunotherapy prevention against this type of pathogen. Cytosolic inflammasome complexes mediated by a pattern recognition receptor (PRR) defend against pathogen infection by activating caspase 1. Pyrin, a candidate PRR, can bind to the inflammasome adaptor ASC to form a caspase 1-activating complex1,2. Mutations in the Pyrin-encoding gene, MEFV, cause a human autoinflammatory disease known as familial Mediterranean fever3,4,5. Despite important roles in immunity and disease, the physiological function of Pyrin remains unknown. Here we show that Pyrin mediates caspase 1 inflammasome activation in response to Rho-glucosylation activity of cytotoxin TcdB6,7,8, a major virulence factor of Clostridium difficile, which causes most cases of nosocomial diarrhoea. The glucosyltransferase-inactive TcdB mutant loses the inflammasome-stimulating activity. Other Rho-inactivating toxins, including FIC-domain adenylyltransferases (Vibrio parahaemolyticus VopS and Histophilus somni IbpA) and Clostridium botulinum ADP-ribosylating C3 toxin, can also biochemically activate the Pyrin inflammasome in their enzymatic activity-dependent manner. These toxins all target the Rho subfamily and modify a switch-I residue. We further demonstrate that Burkholderia cenocepacia inactivates RHOA by deamidating Asn 41, also in the switch-I region, and thereby triggers Pyrin inflammasome activation, both of which require the bacterial type VI secretion system (T6SS). Loss of the Pyrin inflammasome causes elevated intra-macrophage growth of B. cenocepacia and diminished lung inflammation in mice. Thus, Pyrin functions to sense pathogen modification and inactivation of Rho GTPases, representing a new paradigm in mammalian innate immunity.

Abstract: Familial Mediterranean Fever (FMF) is the prototype of a group of inherited inflammatory disorders. The gene (MEFV) responsible for this disease, comprises 10 exons and 781 codons. Twenty-nine mutations, most located in the last exon, have been identified so far. It is unclear whether all are true disease-causing mutations. Five founder mutations, V726A, M694V, M694I, M680I and E148Q account for 74% of FMF chromosomes from typical cases (Armenians, Arabs, Jews, and Turks). Rare mutations are preferentially found in populations not usually affected by FMF (eg Europeans not from the above ancestries). The various combinations of MEFV mutations define severe to mild genotypes. The trend is that genotypes including two mutations located within mutational 'hot-spots' (codons 680 or 694) of the gene are associated with severe phenotypes, whereas mild phenotypes are associated with some other mutations, E148Q being the mildest and least penetrant. Understanding the correlation between the FMF phenotype and genotype is further obscured by the existence of complex alleles, modifier loci, genetic heterogeneity and possible epigenetic factors. Additionally, mutations in the MEFV gene are thought to be involved in non FMF disorders. Carrier rates for FMF mutations may be as high as 1:3 in some populations, suggesting that the disease is underdiagnosed. This review update emphasises that both clinical and genetic features are to be taken into account for patient diagnosis, colchicine treatment and prognosis.