title: Spontaneous retrotransposon insertion into TNF 3'UTR causes heart valve disease and chronic polyarthritis.
abstract: Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) are chronic inflammatory diseases that together affect 2-3% of the population. RA and AS predominantly involve joints, but heart disease is also a common feature in RA and AS patients. Here we have studied a new spontaneous mutation that causes severe polyarthritis in bone phenotype spontaneous mutation 1 (BPSM1) mice. In addition to joint destruction, mutant mice also develop aortic root aneurism and aorto-mitral valve disease that can be fatal depending on the genetic background. The cause of the disease is the spontaneous insertion of a retrotransposon into the 3' untranslated region (3'UTR) of the tumor necrosis factor (TNF), which triggers its strong overexpression in myeloid cells. We found that several members of a family of RNA-binding, CCCH-containing zinc-finger proteins control TNF expression through its 3'UTR, and we identified a previously unidentified regulatory element in the UTR. The disease in BPSM1 mice is independent of the adaptive immune system and does not appear to involve inflammatory cytokines other than TNF. To our knowledge, this is the first animal model showing both polyarthritis and heart disease as a direct result of TNF deregulation. These results emphasize the therapeutic potential of anti-TNF drugs for the treatment of heart valve disease and identify potential therapeutic targets to control TNF expression and inflammation.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3052, Australia;
authors.forename: Derek
authors.initials: D
authors.lastname: Lacey
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3052, Australia;
authors.forename: Peter
authors.initials: P
authors.lastname: Hickey
authors.affiliation: Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Department of Physics, La Trobe University, VIC 3086, Australia;
authors.forename: Benedicta D
authors.initials: BD
authors.lastname: Arhatari
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3052, Australia;
authors.forename: Lorraine A
authors.initials: LA
authors.lastname: O'Reilly
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3052, Australia;
authors.forename: Leona
authors.initials: L
authors.lastname: Rohrbeck
authors.affiliation: Baker IDI Heart and Diabetes Institute, and Central Clinical School, Monash University, Melbourne, VIC 3004, Australia.
authors.forename: Helen
authors.initials: H
authors.lastname: Kiriazis
authors.affiliation: Baker IDI Heart and Diabetes Institute, and Central Clinical School, Monash University, Melbourne, VIC 3004, Australia.
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Du
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3052, Australia; bouillet@wehi.edu.au.
authors.forename: Philippe
authors.initials: P
authors.lastname: Bouillet
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics*; D000783:Aneurysm / Q000473:pathology; D000818:Animals; D001022:Aortic Valve Insufficiency / Q000150:complications / Q000000981:diagnostic imaging / Q000473:pathology; D001168:Arthritis / Q000097:blood / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence; D016026:Bone Marrow Transplantation; D018925:Chemokines / Q000097:blood; D002908:Chronic Disease; D004195:Disease Models, Animal; D005355:Fibrosis; D006349:Heart Valve Diseases / Q000097:blood / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000473:pathology; D007596:Joints / Q000473:pathology; D008817:Mice, Mutant Strains; D008943:Mitral Valve / Q000473:pathology; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D020871:RNA Stability / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018626:Retroelements / Q000235:genetics*; D020086:Short Interspersed Nucleotide Elements / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism; D014463:Ultrasonography; D055114:X-Ray Microtomography; D016335:Zinc Fingers / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D018925:Chemokines; D012333:RNA, Messenger; D018626:Retroelements; D014409:Tumor Necrosis Factor-alpha
keywords: CCCH ZFP; gene regulation; heart valve disease; mRNA stability; rheumatoid arthritis