Comment on: Detection of a rare variant in PSTPIP1 through three generations in a family with an initial diagnosis of FMF/MKD-overlapping phenotype.

Abstract

Dear Editor, We read with great interest the article by Özkılınç Önen et al. that was recently published in Rheumatology [1]. In this impressive article, the authors focused on an interesting issue regarding the genetic puzzle presented in four members of three generations of a Turkish family, with an FMF/mevalonate kinase deficiency (MKD)-overlapping phenotype, who did not carry any MEFV/MVK pathogenic variants. The authors of this article by an elegant approach refined the genetic heterogeneity observed in these patients, by demonstrating the presence of a p. Arg228Cys PSTPIP1 variant in the FMF/MKD phenotype. Notably, PSTPIP1 variants had been also described previously in cases with pyogenic arthritis, pyoderma gangrenosum and Pyogenic Arthritis, Pyoderma gangrenosum and Acne (PAPA) [1]. The results of the aforementioned study [1] contribute significantly in the long-standing, challenging question of the genetic aetiology of FMF, an autosomal, single-gene, recessively inherited disease, characterized by acute, self-limited attacks of fever, serositis and abdominal pain, without any apparent trigger or autoimmune aetiology [2]. The MEFV gene, causing FMF, encodes the protein ‘pyrin’. Considering that no diagnostic biochemical markers are available in FMF thus far, detection of MEFV mutations is a very important issue for an early and correct disease diagnosis. However, the presence of a considerable proportion of FMF cases without MEFV pathogenic variants as well as the high number of heterozygote patients with typical symptoms of the disease have driven a number of alternative aetiopathogenic hypotheses. To this end, our group attempted to elucidate the role of the pyrin-interacting [3], pro-apoptotic protein Siva as a putative mediator of the FMF development. Thus, we hypothesized that mutations in the gene encoding pyrin (MEFV) may affect Siva-mediated apoptosis. Although Siva protein binds pyrin, as shown by transfection and immunoprecipitation experiments, no differences in rates of apoptosis in myeloid cells (THP-1) upon transfection with either wt pyrin or mutant forms of pyrin were observed as assessed by FACS and Western blotting [4]. Therefore, we did not manage to confirm our hypothesis, which would have demonstrated for the first time a connection between apoptosis and inflammation, considering that our experimental results suggested that Siva-mediated unprovoked apoptosis is not likely to be involved in FMF pathogenesis [4]. Moreover, aiming to refine further the molecular basis of FMF, we proceeded in the MEFV knockdown in human myelomonocytic cells in an attempt to identify deregulated microRNAs. Implementation of in silico gene network prediction algorithms and bioinformatics analyses showed that the identified miR-4520a targets genes are implicated in autophagy through regulation of Ras homolog enriched in brain/mammalian target of rapamycin (RHEB/mTOR) signalling, thus demonstrating for the first time the role of deregulated autophagy in the pathogenesis of FMF [5].