Assessment of microRNAs Role in Familial Mediterranean Fever FMF Pathophysiology

Overview

Familial Mediterranean Fever (FMF) genetic diagnosis is well established for homozygous patients. On the other hand, although heterozygous individuals are theoretically healthy carriers, 1/3 of them will develop clinical symptoms of FMF and could benefit from prophylactic treatment. This suggests that the disorder expression mechanisms are not fully elucidated to date. The preliminary results obtained at the Institute for Regenerative Medicine and Biotherapy (IRMB) suggest the involvement of an epigenetic mechanism in FMF pathogenesis, and our laboratory has strong arguments as to the involvement of microRNAs (in particular miR-326) which are negative regulators of gene expression. This study is exploratory and aims to validate the role of miRNAs in the clinical expression of FMF in patients, thus to explore the epigenetic mechanisms that may explain the variability of expression of this disorder.

Familial Mediterranean fever (FMF) is a rare autoinflammatory disorder due to mutations in the MEFV (MEditerranean FeVer) gene, that causes recurrent episodes of fever and acute serositis (peritoneum, pleura, synovium) beginning in early childhood. MEFV gene identification allowed the development of a genomic sequencing test to confirm the diagnosis. The most frequent mutations are M680I, M694V, V726A and M694I, located in exon 10. This gene encodes the protein pyrin, which, following a pro-inflammatory stimulus, is capable of assembling a multi-protein complex to form the pyrin inflammasome. MEFV gene mutations lead to an alteration of its expression in innate immune system cells in FMF patients, causing a dysregulation of the immune response, which results in the abnormal secretion of certain proinflammatory cytokines such as IL-1β and IL-18. FMF is an autosomal recessive disorder. Thus, heterozygous individuals are theoretically healthy carriers. Nevertheless, in nearly 1/3 of patients with clinical symptoms of FMF, a single heterozygous mutation is found. To date, there is no biological marker to distinguish heterozygous individuals who will develop the disease from those who remain healthy carriers, hence diagnostic errors and delays in treatment. Several hypotheses have been put forward to explain this variation in mutation expression, whether it is the environment, the involvement of other genes, or the involvement of epigenetic modifiers. Among the mechanisms that regulate gene expression, microRNAs (miRNAs),which are small non-coding RNAs, negatively regulate gene expression at the post-transcriptional level by binding to sequences located mainly in the region 3'UTR of gene mRNA. Many publications report that they are abnormally expressed in various pathologies. Very recently, this has been reported for FMF. Several studies have focused on miRNAs as biomarkers of FMF, without evaluating their role in FMF pathogenesis. Assessing the role of miRNAs specifically targeting the MEFV gene in myeloid cells (especially monocytes), and the functional impact of their modulation in these cells, would deepen our understanding of FMF physiopathology. If a miRNA specifically targeting MEFV has a proven role in FMF pathophysiology, it could ultimately prove to be a prognostic biomarker of the disorder for heterozygous patients, or even a future therapeutic target.