Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA317491 | ENA |
REPOSITORIES: ENA
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Project description:PFAPA, the syndrome of periodic fever associated with aphthous stomatitis, pharyngitis and/or cervical adenitis, is the most common periodic fever disease in children. Cases are mostly sporadic; the etiopathogenesis is unknown. In order to shed more insights into pathogenesis, we performed microarray expression analysis on samples from patients with PFAPA during and between flares, healthy controls and patients with hereditary autoinflammatory diseases during flares. RNA was extracted from whole peripheral blood from six patients with PFAPA syndrome during flares and asymptomatic intervals, six healthy controls and six patients with hereditary autoinflammatory diseases (2 familial Mediterranean fever (FMF), 1 TNF-receptor-asociated periodic fever syndrome (TRAPS) and 3 cryopyrin-associated periodic syndromes (CAPS)).
2011-06-20 | E-GEOD-17732 | biostudies-arrayexpress
Project description:Hereditary recurrent fevers (HRF) are a group of monogenic autoinflammatory diseases characterized by auto-resolving attacks of sterile inflammation caused by mutations of MEFV, TNFRSF1A and MVK genes1-3. Familial Mediterranean fever (FMF) is the prototype of a HPR and is caused by gain-of-function mutations of the MEFV gene, coding for pyrin4 5. Pyrin is part of the Pyrin-Inflammasome that controls the activation and secretion of interleukin (IL)-1β and can be activated by the cortical actin cytoskeleton remodeling induced by bacterial toxins via RhoA. Mevalonate kinase deficiency (MKD) is secondary to bi-allelic mutations of the gene coding for mevalonate kinase (MVK), an enzyme involved in the cholesterol biosynthesis. Loss-of-function MVK mutations lead to a defective sterol synthesis and to a reduced prenylation of small G proteins, such as RhoA, favoring the activation of the Pyrin-inflammasome6-8. TNF receptor-associated periodic syndrome (TRAPS) is secondary to autosomal dominant mutations of the gene coding for the type I receptor for TNF (TNFRSF1A), resulting in a heap of misfolded TNF receptor 1 in the endoplasmic reticulum, leading to oxidative stress, defective autophagy and consequent over-secretion of pro-inflammatory cytokines9 10. The clinical manifestations of HRFs are rather unspecific and consist mainly in fever, serositis, skin rash, limb and articular pain. No specific biomarkers able to distinguish one among the different HRFs have been identified, so far11. Moreover, the majority of the studies investigating the pathogenic consequences of the genes’ mutations associated with the three HRFs were focused on the few mechanisms classically associated to the pro-inflammatory activation of cells of the innate immunity (NF-kB and MAPK activation, IL-1b activation and secretion). Conversely, an unbiased analysis of possible additional intracellular pathways involved in the different conditions has not been exploited. Recently, large-scale proteomics based on high-resolution mass spectrometry (MS) has offered a systems-wide hypothesis-free method to analyze intracellular pathways in order to identify new disease biomarkers12-14. Here, we analyzed the proteomic signature of unstimulated and stimulated monocytes of patients with FMF, TRAPS and MKD, describing the dysregulated intracellular pathways associated with each condition for the identification of possible biomarkers and possible novel therapeutic targets.
2022-08-12 | PXD024068 | Pride
Project description:Analysis of microRNAs in familial Mediterranean fever
| PRJNA436573 | ENA
Project description:Diet can regulate gene and microRNA (miRNA) expression and various biological processes in the gut. Dietary interventions have been proposed as therapeutic approaches for several diseases, including cancer. In a pilot study, we showed that a low-inflammatory Mediterranean diet reduced markers of local and systemic inflammation in patients with Familial Adenomatous Polyposis (FAP). We evaluated the changes induced by a low-inflammatory Mediterranean dietary intervention on fecal miRNome and intestinal tissue transcriptome in FAP subjects and assessed whether these changes could be associated with the beneficial effects observed in the pilot study. The diet modulated 41 fecal miRNAs, and this modulation remained for three months after the intervention. miR-5092-5p, miR-4527, and miR-3612-3p were positively correlated with adherence to the Mediterranean diet, while miR-6867-5p and miR-760-5p were negatively correlated with serum calprotectin levels. The altered miRNAs target genes mainly related to inflammatory pathways, DNA repair, metabolism, and cytoskeleton organization. Seventy genes were differentially expressed between adenoma and normal tissue. Most were different before the dietary intervention, but reached similar levels after the diet. Functional enrichment analysis identified the proinflammatory ERK1/2, cell cycle regulation and nutrient response pathways as commonly regulated by differentially expressed miRNAs and genes. These findings suggest that fecal miRNAs modulated by the diet reflect an epigenetic regulation occurring in tissues that seems to influence inflammatory pathways. miRNAs and genes with oncogenic and tumor suppressor functions are also regulated, highlighting the potential cancer-preventive effect of the low-inflammatory Mediterranean diet.
2024-01-12 | GSE222298 | GEO
Project description:Diet can regulate gene and microRNA (miRNA) expression and various biological processes in the gut. Dietary interventions have been proposed as therapeutic approaches for several diseases, including cancer. In a pilot study, we showed that a low-inflammatory Mediterranean diet reduced markers of local and systemic inflammation in 27 patients with Familial Adenomatous Polyposis (FAP). We evaluated the changes induced by a low-inflammatory Mediterranean dietary intervention on fecal miRNome and intestinal tissue transcriptome in FAP subjects and assessed whether these changes could be associated with the beneficial effects observed in the pilot study. The diet modulated 41 fecal miRNAs, and this modulation remained for three months after the intervention. miR-5092-5p, miR-4527, and miR-3612-3p were positively correlated with adherence to the Mediterranean diet, while miR-6867-5p and miR-760-5p were negatively correlated with serum calprotectin levels. The altered miRNAs target genes mainly related to inflammatory pathways, DNA repair, metabolism, and cytoskeleton organization. Seventy genes were differentially expressed between adenoma and normal tissue. Most were different before the dietary intervention, but reached similar levels after the diet. Functional enrichment analysis identified the proinflammatory ERK1/2, cell cycle regulation and nutrient response pathways as commonly regulated by differentially expressed miRNAs and genes. These findings suggest that fecal miRNAs modulated by the diet reflect an epigenetic regulation occurring in tissues that seems to influence inflammatory pathways. miRNAs and genes with oncogenic and tumor suppressor functions are also regulated, highlighting the potential cancer-preventive effect of the low-inflammatory Mediterranean diet.
2024-01-12 | GSE218823 | GEO
Project description:Cancer-associated ASXL1 mutations may act as gain-of-function mutations of the ASXL1-BAP1 complex
| PRJNA274361 | ENA
Project description:ALS-Associated KIF5A Mutations Abolish Autoinhibition Resulting in a Toxic Gain of Function
| PRJNA805280 | ENA
Project description:MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression. Heterozygous loss-of-function point mutations of miRNA genes are associated with several human congenital disorders, but neomorphic (gain-of-new-function) mutations in miRNAs due to nucleotide substitutions have not been reported. Here we describe a neomorphic seed region mutation in the chondrocyte-specific, super-enhancer-associated MIR140 gene encoding microRNA-140 (miR-140) in a novel autosomal dominant human skeletal dysplasia. Mice with the corresponding single nucleotide substitution show skeletal abnormalities similar to those of the patients but distinct from those of miR-140-null mice. This mutant miRNA gene yields abundant mutant miR-140-5p expression without miRNA-processing defects. In chondrocytes, the mutation causes widespread derepression of wild-type miR-140-5p targets and repression of mutant miR-140-5p targets, indicating that the mutation produces both loss-of-function and gain-of-function effects. Furthermore, the mutant miR-140-5p seed competes with the conserved RNA-binding protein Ybx1 for overlapping binding sites. This finding may explain the potent target repression and robust in vivo effect by this mutant miRNA even in the absence of evolutionary selection of miRNA–target RNA interactions, which contributes to the strong regulatory effects of conserved miRNAs. Our study presents the first case of a pathogenic gain-of-function miRNA mutation and provides molecular insight into neomorphic actions of emerging and/or mutant miRNAs.
2019-01-29 | GSE116557 | GEO
Project description:MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression. Heterozygous loss-of-function point mutations of miRNA genes are associated with several human congenital disorders, but neomorphic (gain-of-new-function) mutations in miRNAs due to nucleotide substitutions have not been reported. Here we describe a neomorphic seed region mutation in the chondrocyte-specific, super-enhancer-associated MIR140 gene encoding microRNA-140 (miR-140) in a novel autosomal dominant human skeletal dysplasia. Mice with the corresponding single nucleotide substitution show skeletal abnormalities similar to those of the patients but distinct from those of miR-140-null mice. This mutant miRNA gene yields abundant mutant miR-140-5p expression without miRNA-processing defects. In chondrocytes, the mutation causes widespread derepression of wild-type miR-140-5p targets and repression of mutant miR-140-5p targets, indicating that the mutation produces both loss-of-function and gain-of-function effects. Furthermore, the mutant miR-140-5p seed competes with the conserved RNA-binding protein Ybx1 for overlapping binding sites. This finding may explain the potent target repression and robust in vivo effect by this mutant miRNA even in the absence of evolutionary selection of miRNA–target RNA interactions, which contributes to the strong regulatory effects of conserved miRNAs. Our study presents the first case of a pathogenic gain-of-function miRNA mutation and provides molecular insight into neomorphic actions of emerging and/or mutant miRNAs.
2019-01-29 | GSE98306 | GEO