Transcriptional repression and differential splicing of Fas mRNA by early transposon (ETn) insertion in autoimmune lpr mice

Abstract

Lpr (lymphoproliferation) is a recessive trait caused by a mutation in the Fas gene which reduces the Fas transcript substantially. When reverse transcription polymerase chain reaction (RT-PCR) was performed using pairs of primers surrounding a particular portion of Fas mRNA, wild-type and approximately 180 base pair (bp) longer PCR products were consistently generated from lpr thymocytes. The latter contained an insertion of 183 nucleotides which was 98.9% homologous to early transposon (ETn) which was found in an immunoglobulin switch region of murine plasmacytoma, P3.26Bu4. These data clearly indicate that ETn insertion into the Fas gene intron causes transcriptional repression. However, this defect may be leaky due to the production of intact Fas mRNA by splicing out ETn-containing intron from primary Fas transcripts. The inserted 183 bp fragment has a potential to code in-frame 61 amino acids, so that the mutant Fas antigen may also be produced. Low level expression of wild-type and mutant Fas antigens may be relevant to the variable phenotype in lpr mice.