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THU0092 The l1 mrna in rheumatoid arthritis encodes a functional retrotransposable element
  1. M Neidhart1,
  2. J Rethage1,
  3. O Distler1,
  4. MT Peyer2,
  5. ME Billingham3,
  6. BA Michel1,
  7. RE Gay1,
  8. S Gay1
  1. 1Rheumatology, University Hospital, Zurich, Switzerland
  2. 2Institute for Plant Physiology, University of Montreal, Montreal, Canada
  3. 3Veterinary School, University of Bristol, Bristol, UK

Abstract

Background L1 retrotransposons have been detected in rheumatoid arthritis (RA) at sites of joint destruction.

Objectives To caracterise the L1 mRNA in RA.

Methods RNA was isolated from the synovial tissue of a 35-years old woman with RA. The complete L1 sequence was determined by 3?/5?-RACE and compared with functional L1 retrotransposons in plants, animals and humans using 50% consensus trees of the elements and the neighbour-joining method. Methylation of the genomic 5?UTR was determined by the sodium-disulfite/PCR method. In situ hybridization was performed on synovial tissues with riboprobes recognising the ORF1 of this element to detect intact L1 elements.

Results A complete L1 mRNA was obtained with the 5?UTR (including a hypoxia inducing factor-responding element and numerous CpG islands), an ORF1 (encoding the p40/RNA binding protein) and an ORF2 (encoding the p150/endonuclease and reverse transcriptase protein). In RA, the genomic 5?UTR appeared hypomethylated, compared to normal control DNA. In situ hybridization showed that the L1 ORF1 transcript is expressed in the sub-lining of patients with RA. Phylogenic trees showed that the 5?UTR nucleotide sequence and the ORF1 peptide sequence have high similarities with human L1.39 and L1.25, two functional L1 retrotransposons, and the ORF2 peptide sequence resembled the M22334 L1 insertion in type A haemophilia. The endonuclease region of ORF2 appears to be highly conserved in functional L1s, but as shown by a phylogenic tree, the small difference appears to be a specific marker for evolution, discriminating L1s in plants, rodents, primates and humans.

Conclusion Intact L1 elements are expressed in the synovial tissue of patients with RA most likely following hypomethylation of their 5?UTR. The L1 mRNA transcript belongs to the functional L1 retrotransposons, including elements producing insertional mutations. Thus, functional L1s could be involved in the transformed phenotype of some synovial cells.

Reference

  1. Neidhart M, et al. Arthritis Rheum. 2000;43:2634–47

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