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-1 mice 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 this subpopulation of CF-1 mice. The size of mdr-3 mRNA transcript from ivermectin-sensitive mutant mice was different from that of wild-type mice. Sequence 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 terminal 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 reported case of a gene mutation induced by a solo retroviral LTR with a phenotypic consequence in the mouse, and may provide new insights into the understanding of the effects of viral solo LTR sequences on mammalian gene expression.
Jun
K
K
National CRI Center for Calcium and Learning, Pohang University of Science and Technology, Pohang, 790-784, Republic of Korea.
Lee
S B
SB
Shin
H S
HS
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D001482:Base Composition; D004247:DNA / Q000032:analysis; D004342:Drug Hypersensitivity / Q000235:genetics; D007438:Introns / Q000235:genetics; D007559:Ivermectin / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D009410:Nerve Degeneration / Q000139:chemically induced / Q000473:pathology; D012326:RNA Splicing / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics*; D012689:Sequence Homology, Nucleic Acid; D020079:Terminal Repeat Sequences / Q000235:genetics*
D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D012333:RNA, Messenger; D007559:Ivermectin; D004247:DNA; C095122:multidrug resistance protein 3