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Open AccessArticle

Identification of New, Functionally Relevant Mutations in the Coding Regions of the Human Fos and Jun Proto-Oncogenes in Rheumatoid Arthritis Synovial Tissue

1
Experimental Rheumatology Unit, Department of Orthopedics, Jena University Hospital, Waldkliniken Eisenberg GmbH, 07607 Eisenberg, Germany
2
Institute of Clinical Chemistry, Hannover Medical School, 30625 Hannover, Germany
3
Structural and Computational Biology Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany
4
Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, 04103 Leipzig, Germany
5
Department for Cell Therapy, Fraunhofer Institute for Cell Therapy and Immunology, 04103 Leipzig, Germany
6
Division of Experimental Virology, Institute for Medical Microbiology, Jena University Hospital, Friedrich Schiller University, 07747 Jena, Germany
7
Institute of Transfusion Medicine, Jena University Hospital, 07747 Jena, Germany
8
Department of Internal Medicine III, Division of Rheumatology & Osteology, Jena University Hospital, 07747 Jena, Germany
9
Division of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Corporate Member of Berlin Institute of Health, Freie Universität and Humboldt-Universität, 10117 Berlin, Germany
10
Translational Centre for Regenerative Medicine, University of Leipzig, 04103 Leipzig, Germany
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Present Address: Institute of Transfusion Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Received: 30 October 2020 / Revised: 16 December 2020 / Accepted: 22 December 2020 / Published: 23 December 2020
(This article belongs to the Section Medical Research)
In rheumatoid arthritis (RA), the expression of many pro-destructive/pro-inflammatory proteins depends on the transcription factor AP-1. Therefore, our aim was to analyze the presence and functional relevance of mutations in the coding regions of the AP-1 subunits of the fos and jun family in peripheral blood (PB) and synovial membranes (SM) of RA and osteoarthritis patients (OA, disease control), as well as normal controls (NC). Using the non-isotopic RNAse cleavage assay, one known polymorphism (T252C: silent; rs1046117; present in RA, OA, and NC) and three novel germline mutations of the cfos gene were detected: (i) C361G/A367G: Gln121Glu/Ile123Val, denoted as “fos121/123”; present only in one OA sample; (ii) G374A: Arg125Lys, “fos125”; and (iii) C217A/G374A: Leu73Met/Arg125Lys, “fos73/125”, the latter two exclusively present in RA. In addition, three novel somatic cjun mutations (604–606ΔCAG: ΔGln202, “jun202”; C706T: Pro236Ser, “jun236”; G750A: silent) were found exclusively in the RA SM. Tansgenic expression of fos125 and fos73/125 mutants in NIH-3T3 cells induced an activation of reporter constructs containing either the MMP-1 (matrix metalloproteinase) promoter (3- and 4-fold, respectively) or a pentameric AP-1 site (approximately 5-fold). Combined expression of these two cfos mutants with cjun wildtype or mutants (jun202, jun236) further enhanced reporter expression of the pentameric AP-1 construct. Finally, genotyping for the novel functionally relevant germline mutations in 298 RA, 288 OA, and 484 NC samples revealed no association with RA. Thus, functional cfos/cjun mutants may contribute to local joint inflammation/destruction in selected patients with RA by altering the transactivation capacity of AP-1 complexes. View Full-Text
Keywords: rheumatoid arthritis; synovial membrane; fibroblast-like synoviocytes; transcription factor; AP-1; Jun; Fos; mutation; polymorphism rheumatoid arthritis; synovial membrane; fibroblast-like synoviocytes; transcription factor; AP-1; Jun; Fos; mutation; polymorphism
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MDPI and ACS Style

Huber, R.; Augsten, S.; Kirsten, H.; Zell, R.; Stelzner, A.; Thude, H.; Eidner, T.; Stuhlmüller, B.; Ahnert, P.; Kinne, R.W. Identification of New, Functionally Relevant Mutations in the Coding Regions of the Human Fos and Jun Proto-Oncogenes in Rheumatoid Arthritis Synovial Tissue. Life 2021, 11, 5. https://doi.org/10.3390/life11010005

AMA Style

Huber R, Augsten S, Kirsten H, Zell R, Stelzner A, Thude H, Eidner T, Stuhlmüller B, Ahnert P, Kinne RW. Identification of New, Functionally Relevant Mutations in the Coding Regions of the Human Fos and Jun Proto-Oncogenes in Rheumatoid Arthritis Synovial Tissue. Life. 2021; 11(1):5. https://doi.org/10.3390/life11010005

Chicago/Turabian Style

Huber, René; Augsten, Sandra; Kirsten, Holger; Zell, Roland; Stelzner, Axel; Thude, Hansjörg; Eidner, Thorsten; Stuhlmüller, Bruno; Ahnert, Peter; Kinne, Raimund W. 2021. "Identification of New, Functionally Relevant Mutations in the Coding Regions of the Human Fos and Jun Proto-Oncogenes in Rheumatoid Arthritis Synovial Tissue" Life 11, no. 1: 5. https://doi.org/10.3390/life11010005

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