Spontaneous retrotransposon insertion into TNF 3'UTR causes heart valve disease and chronic polyarthritis

Proc Natl Acad Sci U S A. 2015 Aug 4;112(31):9698-703. doi: 10.1073/pnas.1508399112. Epub 2015 Jul 20.


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.

Keywords: CCCH ZFP; gene regulation; heart valve disease; mRNA stability; rheumatoid arthritis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics*
  • Aneurysm / pathology
  • Animals
  • Aortic Valve Insufficiency / complications
  • Aortic Valve Insufficiency / diagnostic imaging
  • Aortic Valve Insufficiency / pathology
  • Arthritis / blood
  • Arthritis / diagnostic imaging
  • Arthritis / genetics*
  • Arthritis / pathology
  • Base Sequence
  • Bone Marrow Transplantation
  • Chemokines / blood
  • Chronic Disease
  • Disease Models, Animal
  • Fibrosis
  • Heart Valve Diseases / blood
  • Heart Valve Diseases / diagnostic imaging
  • Heart Valve Diseases / genetics*
  • Heart Valve Diseases / pathology
  • Humans
  • Inflammation / pathology
  • Joints / pathology
  • Mice, Mutant Strains
  • Mitral Valve / pathology
  • Molecular Sequence Data
  • Mutagenesis, Insertional / genetics*
  • Mutation / genetics*
  • RNA Stability / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Retroelements / genetics*
  • Short Interspersed Nucleotide Elements / genetics
  • Tumor Necrosis Factor-alpha / genetics*
  • Tumor Necrosis Factor-alpha / metabolism
  • Ultrasonography
  • X-Ray Microtomography
  • Zinc Fingers / genetics


  • 3' Untranslated Regions
  • Chemokines
  • RNA, Messenger
  • Retroelements
  • Tumor Necrosis Factor-alpha