THE DEFECT IN FAS MESSENGER-RNA EXPRESSION IN MRL LPR MICE IS ASSOCIATED WITH INSERTION OF THE RETROTRANSPOSON, ETN

Fas is a cell surface protein of the tumor necrosis factor receptor, n erve growth factor receptor, CD40 family, and is involved in the contr ol of lymphocyte apoptosis. A mutation in the Fas gene in MRL/lpr mice results in massive lymphoproliferation (lpr) and accelerated autoimmu nity. To further study the nature of this defect, Fas mRNA expression was evaluated by reverse transcriptase polymerase chain reaction as we ll as by Northern blotting. These studies revealed that the wild-type Fas message was produced at approximately 10-fold lower levels in the lpr compared with the + + substrain) of MRL mice. In addition to the w ild-type transcript, lpr mice also synthesized chimeric transcripts co ntaining an insertion of the early retrotransposon (ETn). Molecular cl oning and nucleotide sequencing of a Fas-ETn chimeric cDNA suggested t hat the striking reduction in wild-type Fas mRNA levels and the presen ce of aberrant transcripts in MRL/lpr mice are most likely explained b y the insertion of the ETn retrotransposon into an intron of the Fas g ene and induction of alternative splicing involving the 5' ETn long te rminal repeat.