Familial Mediterranean Fever (FMF) and FMF-like diseases: From genetics to functional diagnostic tests – FMFgeneToDiag

Familial Mediterranean fever (FMF) is the most common hereditary systemic auto-inflammatory disease, classically transmitted as an autosomal recessive trait. This disease, which is particularly frequent in populations of Middle Eastern Mediterranean extraction, is also described in several other populations. Given the absence of pathognomonic clinical symptoms and of any specific biochemical abnormality, the diagnosis of FMF has been for many years one of exclusion, being entirely based on clinical criteria. It is, however, of prime importance to ascertain this diagnosis because (i) the symptomatology of FMF may mimic that of other affections—such as acute infectious peritonitis, appendicitis, cholecystitis, or arthritis—thereby leading to unnecessary invasive investigations, (ii) an effective therapy is available: colchicine therapy reduces the frequency and severity of the inflammatory attacks, and (iii) the most severe complication of FMF is amyloidosis, mainly renal, which, in the absence of daily and lifelong administration of colchicine, develops over years and progresses to terminal renal failure. The discovery of biallelic mutations in the MEFV gene (encoding the inflammasome sensor, Pyrin) from FMF patients has provided the first objective diagnostic criterion, the Pyrin inflammasome being an innate immune platform leading to caspase-1 activation, IL-1ß release and an inflammatory cell death termed pyroptosis. However, in spite of this gene discovery, the establishment of a formal diagnosis of FMF remains an important issue for the following reasons: virtually all MEFV sequence variants described in humans are missense variations, their clinical relevance and their functional consequences on the Pyrin inflammasome responses remain unclear. Furthermore, ~ 30% of the patients with a clinical diagnosis of FMF present a single mutated MEFV allele, while in ~ 10% of the patients, no MEFV mutation is detected. Finally, even for patients with unambiguous genetic diagnosis (bi-allelic clearly pathogenic MEFV variants), the final diagnosis can happen after a long delay. There is thus a need to develop new tools to increase the rapidity and decrease the uncertainty of FMF diagnosis. A better understanding of the genetic and immune bases of FMF and FMF-like (in which no or a single MEFV variant is identified) diseases is needed. Our multidisciplinary consortium combines a unique expertise in the management of the disease (National Reference Center for FMF), and in the field of auto-inflammation: in human genetics, molecular and cell biology, and single cell analysis. Thanks to such synergistic clinical and experimental approaches, we will 1-assess the functional impact of the different MEFV variants on the Pyrin inflammasome, 2-combine genetics and functional single cells approaches to search for somatic MEFV mutations, 3-identify and characterize novel genes mutated in patients with an FMF-like disease, 4-develop a rapid inflammasome-based diagnostic test for FMF. This project should allow a better understanding of the Pyrin inflammasome (function and dysfunctions), and of the genotype-phenotype correlation in FMF and FMF-like patients. Furthermore, this translational project should lead to a rapid functional diagnostic test for FMF, which should be of great benefits for both the patient and the healthcare system.