Differential Expression of miR-4520a Associated With Pyrin Mutations in Familial Mediterranean Fever (FMF)

Helen Latsoudis, Mir Farzin Mashreghi, Joachim R. Grün, Hyun Dong Chang, Bruno Stuhlmüller, Argyro Repa, Irini Gergiannaki, Eleni Kabouraki, George S. Vlachos, Thomas Häupl, Andreas Radbruch, Prodromos Sidiropoulos, Kimon Doukoumetzidis, Dimitris Kardassis, Timothy B. Niewold, Dimitrios T. Boumpas, George N. Goulielmos

Research output: Contribution to journalArticle

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Abstract

Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurrent, acute, and self-limiting attacks of fever. Mutations in MEFV gene encoding pyrin account for FMF, but the high number of heterozygote patients with typical symptoms of the disease has driven a number of alternative aetiopathogenic hypotheses. The MEFV gene was knocked down in human myelomonocytic cells that express endogenous pyrin to identify deregulated microRNAs (miRNAs). Microarray analyses revealed 29 significantly differentially expressed miRNAs implicated in pathways associated with cellular integrity and survival. Implementation of in silico gene network prediction algorithms and bioinformatics analyses showed that miR-4520a is predicted to target genes implicated in autophagy through regulation of RHEB/mTOR signaling. Differential expression levels of RHEB were confirmed by luciferase reporter gene assays providing further evidence that is directly targeted by miR-4520a. Although the relative expression levels of miR-4520a were variable among FMF patients, the statistical expression of miR-4520a was different between FMF mutation carriers and controls (P=0.0061), indicating an association between miR-4520a expression and MEFV mutations. Comparison between FMF patients bearing the M694V mutation, associated with severe disease, and healthy controls showed a significant increase in miR-4520a expression levels (P=0.00545). These data suggest that RHEB, the main activator of mTOR signaling, is a valid target of miR-4520a with the relative expression levels of the latter being significantly deregulated in FMF patients and highly dependent on the presence of pyrin mutations, especially of the M694V type. These results suggest a role of deregulated autophagy in the pathogenesis of FMF.

Original languageEnglish (US)
JournalJournal of Cellular Physiology
DOIs
StateAccepted/In press - 2016

Fingerprint

Familial Mediterranean Fever
Genes
Mutation
MicroRNAs
Bearings (structural)
Autophagy
Gene encoding
Bioinformatics
Microarrays
Luciferases
Assays
Association reactions
Gene Regulatory Networks
Microarray Analysis
Heterozygote
Pyrin
Computational Biology
Reporter Genes
Computer Simulation
Fever

ASJC Scopus subject areas

  • Medicine(all)
  • Physiology
  • Clinical Biochemistry
  • Cell Biology

Cite this

Latsoudis, H., Mashreghi, M. F., Grün, J. R., Chang, H. D., Stuhlmüller, B., Repa, A., ... Goulielmos, G. N. (Accepted/In press). Differential Expression of miR-4520a Associated With Pyrin Mutations in Familial Mediterranean Fever (FMF). Journal of Cellular Physiology. https://doi.org/10.1002/jcp.25602

Differential Expression of miR-4520a Associated With Pyrin Mutations in Familial Mediterranean Fever (FMF). / Latsoudis, Helen; Mashreghi, Mir Farzin; Grün, Joachim R.; Chang, Hyun Dong; Stuhlmüller, Bruno; Repa, Argyro; Gergiannaki, Irini; Kabouraki, Eleni; Vlachos, George S.; Häupl, Thomas; Radbruch, Andreas; Sidiropoulos, Prodromos; Doukoumetzidis, Kimon; Kardassis, Dimitris; Niewold, Timothy B.; Boumpas, Dimitrios T.; Goulielmos, George N.

In: Journal of Cellular Physiology, 2016.

Research output: Contribution to journalArticle

Latsoudis, H, Mashreghi, MF, Grün, JR, Chang, HD, Stuhlmüller, B, Repa, A, Gergiannaki, I, Kabouraki, E, Vlachos, GS, Häupl, T, Radbruch, A, Sidiropoulos, P, Doukoumetzidis, K, Kardassis, D, Niewold, TB, Boumpas, DT & Goulielmos, GN 2016, 'Differential Expression of miR-4520a Associated With Pyrin Mutations in Familial Mediterranean Fever (FMF)', Journal of Cellular Physiology. https://doi.org/10.1002/jcp.25602
Latsoudis, Helen ; Mashreghi, Mir Farzin ; Grün, Joachim R. ; Chang, Hyun Dong ; Stuhlmüller, Bruno ; Repa, Argyro ; Gergiannaki, Irini ; Kabouraki, Eleni ; Vlachos, George S. ; Häupl, Thomas ; Radbruch, Andreas ; Sidiropoulos, Prodromos ; Doukoumetzidis, Kimon ; Kardassis, Dimitris ; Niewold, Timothy B. ; Boumpas, Dimitrios T. ; Goulielmos, George N. / Differential Expression of miR-4520a Associated With Pyrin Mutations in Familial Mediterranean Fever (FMF). In: Journal of Cellular Physiology. 2016.
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abstract = "Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurrent, acute, and self-limiting attacks of fever. Mutations in MEFV gene encoding pyrin account for FMF, but the high number of heterozygote patients with typical symptoms of the disease has driven a number of alternative aetiopathogenic hypotheses. The MEFV gene was knocked down in human myelomonocytic cells that express endogenous pyrin to identify deregulated microRNAs (miRNAs). Microarray analyses revealed 29 significantly differentially expressed miRNAs implicated in pathways associated with cellular integrity and survival. Implementation of in silico gene network prediction algorithms and bioinformatics analyses showed that miR-4520a is predicted to target genes implicated in autophagy through regulation of RHEB/mTOR signaling. Differential expression levels of RHEB were confirmed by luciferase reporter gene assays providing further evidence that is directly targeted by miR-4520a. Although the relative expression levels of miR-4520a were variable among FMF patients, the statistical expression of miR-4520a was different between FMF mutation carriers and controls (P=0.0061), indicating an association between miR-4520a expression and MEFV mutations. Comparison between FMF patients bearing the M694V mutation, associated with severe disease, and healthy controls showed a significant increase in miR-4520a expression levels (P=0.00545). These data suggest that RHEB, the main activator of mTOR signaling, is a valid target of miR-4520a with the relative expression levels of the latter being significantly deregulated in FMF patients and highly dependent on the presence of pyrin mutations, especially of the M694V type. These results suggest a role of deregulated autophagy in the pathogenesis of FMF.",
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AU - Latsoudis, Helen

AU - Mashreghi, Mir Farzin

AU - Grün, Joachim R.

AU - Chang, Hyun Dong

AU - Stuhlmüller, Bruno

AU - Repa, Argyro

AU - Gergiannaki, Irini

AU - Kabouraki, Eleni

AU - Vlachos, George S.

AU - Häupl, Thomas

AU - Radbruch, Andreas

AU - Sidiropoulos, Prodromos

AU - Doukoumetzidis, Kimon

AU - Kardassis, Dimitris

AU - Niewold, Timothy B.

AU - Boumpas, Dimitrios T.

AU - Goulielmos, George N.

PY - 2016

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N2 - Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurrent, acute, and self-limiting attacks of fever. Mutations in MEFV gene encoding pyrin account for FMF, but the high number of heterozygote patients with typical symptoms of the disease has driven a number of alternative aetiopathogenic hypotheses. The MEFV gene was knocked down in human myelomonocytic cells that express endogenous pyrin to identify deregulated microRNAs (miRNAs). Microarray analyses revealed 29 significantly differentially expressed miRNAs implicated in pathways associated with cellular integrity and survival. Implementation of in silico gene network prediction algorithms and bioinformatics analyses showed that miR-4520a is predicted to target genes implicated in autophagy through regulation of RHEB/mTOR signaling. Differential expression levels of RHEB were confirmed by luciferase reporter gene assays providing further evidence that is directly targeted by miR-4520a. Although the relative expression levels of miR-4520a were variable among FMF patients, the statistical expression of miR-4520a was different between FMF mutation carriers and controls (P=0.0061), indicating an association between miR-4520a expression and MEFV mutations. Comparison between FMF patients bearing the M694V mutation, associated with severe disease, and healthy controls showed a significant increase in miR-4520a expression levels (P=0.00545). These data suggest that RHEB, the main activator of mTOR signaling, is a valid target of miR-4520a with the relative expression levels of the latter being significantly deregulated in FMF patients and highly dependent on the presence of pyrin mutations, especially of the M694V type. These results suggest a role of deregulated autophagy in the pathogenesis of FMF.

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