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7 Publications visible to you, out of a total of 7
Association of Inflammasome Gene Expression Levels with Pathogenesis of Familial Mediterranean Fever in Armenians

Abstract (Expand)

Mediterranean fever (FMF) is a genetically determined autoinflammatory disease transmitted mostly by an autosomal recessive mechanism and caused by point mutations of the MEFV (Mediterranean FeVer) … gene. The aim of this study was to evaluate the expression of inflammasome genes (p65, Casp1, MEFV, and NLRP3) in patients with FMF compared to controls to understand the changes playing a key role in disease development. We found altered expression levels of the full-length MEFV isoform as well as Casp1 and p65 in FMF patients versus controls. This, once again, highlighted the significance of inflammasome genes in terms of FMF.

Authors: Varduhi Hayrapetyan, Lana Karapetyan, Lilit Ghukasyan, Sofi Atshemyan, Hovsep Ghazaryan, Valentina Vardanyan, Vahan Mukuchyan, Arsen Arakelyan, Roksana Zakharyan

Date Published: 2nd Dec 2024

Publication Type: Journal

Genewise detection of variants in MEFV gene using nanopore sequencing

Abstract (Expand)

Mediterranean Fever (FMF) is a genetic disorder with complex inheritance patterns and genotype-phenotype associations, and it is highly prevalent in Armenia. FMF typically follows an autosomal recessive … inheritance pattern (OMIM: 249100), though it can occasionally display a rare dominant inheritance pattern with variable penetrance (OMIM։134610). The disease is caused by mutations in the MEFV gene, which encodes the pyrin protein. While the 26 most prevalent mutations account for nearly 99% of all FMF cases, more than 60 pathogenic mutations have been identified. In this study, we aimed to develop an affordable nanopore sequencing method for full-length MEFV gene mutation detection to aid in the diagnosis and screening of FMF. We employed a multiplex amplicon sequencing approach, allowing for the processing of up to 12 samples on both Flow cells and Flongle flow cells. The results demonstrated near-complete concordance between nanopore variant calling and qPCR genotypes. Moreover, nanopore sequencing identified additional variants, which were confirmed by whole exome sequencing. Additionally, intronic and UTR variants were detected. Our findings demonstrate the feasibility of full-gene nanopore sequencing for detecting FMF-associated pathogenic variants. The method is cost-effective, with costs comparable to those of the qPCR test, making it particularly suitable for settings with limited laboratory infrastructure. Further clinical validation using larger sample cohorts will be necessary.

Authors: Lilit Ghukasyan, Gisane Khachatryan, Tamara Sirunyan, Arpine Minasyan, Siras Hakobyan, Andranik Chavushyan, Varduhi Hayrapetyan, Hovsep Ghazaryan, Gevorg Martirosyan, Gohar Mkrtchyan, Valentina Vardanyan, Vahan Mukuchyan, Ashot Davidyants, Roksana Zakharyan, Arsen Arakelyan

Date Published: 29th Nov 2024

Publication Type: Journal

Generation of iPSCs from a Patient with the M694V Mutation in the MEFV Gene Associated with Familial Mediterranean Fever and Their Differentiation into Macrophages.

Abstract (Expand)

Familial Mediterranean fever (FMF) is a systemic autoinflammatory disorder caused by inherited mutations in the MEFV (Mediterranean FeVer) gene, located on chromosome 16 (16p13.3) and encoding the pyrin … protein. Despite the existing data on MEFV mutations, the exact mechanism of their effect on the development of the pathological processes leading to the spontaneous and recurrent autoinflammatory attacks observed in FMF, remains unclear. Induced pluripotent stem cells (iPSCs) are considered an important tool to study the molecular genetic mechanisms of various diseases due to their ability to differentiate into any cell type, including macrophages, which contribute to the development of FMF. In this study, we developed iPSCs from an Armenian patient with FMF carrying the M694V, p.(Met694Val) (c.2080A>G, rs61752717) pathogenic mutation in exon 10 of the MEFV gene. As a result of direct differentiation, macrophages expressing CD14 and CD45 surface markers were obtained. We found that the morphology of macrophages derived from iPSCs of a patient with the MEFV mutation significantly differed from that of macrophages derived from iPSCs of a healthy donor carrying the wild-type MEFV gene. Keywords: Familial Mediterranean fever; MEFV gene; differentiation; macrophages; patient-specific induced pluripotent stem cells.

Authors: Elena V Grigor'eva, Lana V Karapetyan, Anastasia A Malakhova, Sergey P Medvedev, Julia M Minina, Varduhi H Hayrapetyan, Valentina S Vardanyan, Suren M Zakian, Arsen Arakelyan, Roksana Zakharyan

Date Published: 2024

Publication Type: Journal

Generation of three induced pluripotent stem cell lines (RAUi001-A, RAUi001-B and RAUi001-C) from peripheral blood mononuclear cells of a healthy Armenian individual.

Abstract (Expand)

The study of pathological processes in cells carrying mutations should be carried out in comparison with a healthy control group. Familial Mediterranean fever (FMF), which is caused by a mutation in … the MEFV gene, is predominantly found in people of Armenian nationality with the prevalence of 14–100 per 10000. We have obtained induced pluripotent stem cells (iPSCs) from Armenian healthy patient, which will be included as a control group in the study of this disease. iPSCs rapidly proliferate in colonies of cells with a typical pluripotent-like morphology, have a normal karyotype (46,XX). iPSCs express pluripotency markers (OCT4, SOX2, TRA-1–60, NANOG) and are able to give derivatives of three germ layers.

Authors: Elena V. Grigor’eva, Anastasia A. Malakhova, Lilit Ghukasyan, Varduhi Hayrapetyan, Sofi Atshemyan, Valentina Vardanyan, Suren M. Zakian, Roksana Zakharyan, Arsen Arakelyan

Date Published: 17th Jun 2023

Publication Type: Journal

Systemic Concentrations of Short Chain Fatty Acids Are Elevated in Salmonellosis and Exacerbation of Familial Mediterranean Fever.

Abstract (Expand)

Gut microbiota-produced short chain fatty acids (SCFAs) play an important role in the normal human metabolism and physiology. Although the gradients of SCFAs from the large intestine, where they are … largely produced, to the peripheral blood as well as the main routes of SCFA metabolism by different organs are known well for the healthy state, there is a paucity of information regarding how these are affected in disease. In particular, how the inflammation caused by infection or autoinflammatory disease affect the concentration of SCFAs in the peripheral venous blood. In this work, we revealed that diseases caused either by infectious agents (two Salmonella enterica serovars, S. Enteritidis, and S. Typhimurium) or by the exacerbation of an autoinflammatory disease, familial Mediterranean fever (FMF), both result in a significantly elevated systemic concentration of SCFAs. In the case of salmonellosis the concentration of SCFAs in peripheral blood was significantly and consistently higher, from 5- to 20-fold, compared to control. In the case of FMF, however, a significant increase of SCFAs in the peripheral venous blood was detected only in the acute phase of the disease, with a lesser impact in remission. It seems counterintuitive that the dysbiotic conditions, with a reduced number of gut microorganisms, produce such an effect. This phenomenon, however, must be appraised within the context of how the inflammatory diseases affect the normal physiology. We discuss a number of factors that may contribute to the "leak" and persistence of gut-produced SCFAs into the systemic circulation in infectious and autoinflammatory diseases.

Authors: Zhanna A Ktsoyan, Mkhitar S Mkrtchyan, Magdalina K Zakharyan, Armine A Mnatsakanyan, Karine A Arakelova, Zaruhi U Gevorgyan, Anahit M Sedrakyan, Alvard I Hovhannisyan, Arsen A Arakelyan, Rustam I Aminov

Date Published: 24th May 2016

Publication Type: Journal

Management of familial Mediterranean fever by colchicine does not normalize the altered profile of microbial long chain fatty acids in the human metabolome.

Abstract (Expand)

In our previous works we established that in an autoinflammatory condition, familial Mediterranean fever (FMF), the gut microbial diversity is specifically restructured, which also results in the altered … profiles of microbial long chain fatty acids (LCFAs) present in the systemic metabolome. The mainstream management of the disease is based on oral administration of colchicine to suppress clinical signs and extend remission periods and our aim was to determine whether this therapy normalizes the microbial LCFA profiles in the metabolome as well. Unexpectedly, the treatment does not normalize these profiles. Moreover, it results in the formation of new distinct microbial LCFA clusters, which are well separated from the corresponding values in healthy controls and FMF patients without the therapy. We hypothesize that the therapy alters the proinflammatory network specific for the disease, with the concomitant changes in gut microbiota and the corresponding microbial LCFAs in the metabolome.

Authors: Zhanna A Ktsoyan, Natalia V Beloborodova, Anahit M Sedrakyan, George A Osipov, Zaruhi A Khachatryan, Gayane P Manukyan, Karine A Arakelova, Alvard I Hovhannisyan, Arsen A Arakelyan, Karine A Ghazaryan, Magdalina K Zakaryan, Rustam I Aminov

Date Published: 28th Jan 2013

Publication Type: Journal

Profiles of Microbial Fatty Acids in the Human Metabolome are Disease-Specific.

Abstract (Expand)

The human gastrointestinal tract is inhabited by a diverse and dense symbiotic microbiota, the composition of which is the result of host-microbe co-evolution and co-adaptation. This tight integration … creates intense cross-talk and signaling between the host and microbiota at the cellular and metabolic levels. In many genetic or infectious diseases the balance between host and microbiota may be compromised resulting in erroneous communication. Consequently, the composition of the human metabolome, which includes the gut metabolome, may be different in health and disease states in terms of microbial products and metabolites entering systemic circulation. To test this hypothesis, we measured the level of hydroxy, branched, cyclopropyl and unsaturated fatty acids, aldehydes, and phenyl derivatives in blood of patients with a hereditary autoinflammatory disorder, familial Mediterranean fever (FMF), and in patients with peptic ulceration (PU) resulting from Helicobacter pylori infection. Discriminant function analysis of a data matrix consisting of 94 cases as statistical units (37 FMF patients, 14 PU patients, and 43 healthy controls) and the concentration of 35 microbial products in the blood as statistical variables revealed a high accuracy of the proposed model (all cases were correctly classified). This suggests that the profile of microbial products and metabolites in the human metabolome is specific for a given disease and may potentially serve as a biomarker for disease.

Authors: Zhanna A Ktsoyan, Natalia V Beloborodova, Anahit M Sedrakyan, George A Osipov, Zaruhi A Khachatryan, Denise Kelly, Gayane P Manukyan, Karine A Arakelova, Alvard I Hovhannisyan, Andrey Y Olenin, Arsen A Arakelyan, Karine A Ghazaryan, Rustam I Aminov

Date Published: 20th Jan 2011

Publication Type: Journal

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