Insertion of a retroviral solo long terminal repeat in mdr-3 locus disrupts mRNA splicing in mice

Previously, the abermectin-induced neurotoxicity of subpopulation of CF-I m ice was shown to be caused by the deficiency of mdr-3 P-glycoprotein. Here, we have characterized the molecular nature of the mdr-3 gene mutation in t his subpopulation of CF-1 mice. The size of mdr-3 mRNA transcript from iver mectin-sensitive mutant mice was different from that of wild-type mice. Seq uence analysis of RT-PCR products isolated from the mutant brain disclosed that the exon 23 of the mdr-3 gene is deleted or altered in the transcripts . The analysis of the genomic locus revealed an insertion of a solo long te rminal repeat (:LTR) of the ecotropic murine leukemia virus in the reverse orientation in the intron of the mdr-3 gene, causing abnormal splicing and thereby disrupting the mdr-3 gene function. In addition, histopathological analysis of the brains of the ivermectin-treated mutants revealed selective neuronal degeneration in the hippocampal CA3 region. This is the first rep orted case of a gene mutation induced. by a solo retroviral LTR with a phen otypic consequence in the mouse, and may provide new insights into the unde rstanding of the effects of viral solo LTR sequences on mammalian gene expr ession.