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

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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Mammalian Genome Springer Journals

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

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Publisher
Springer-Verlag
Copyright
Copyright © 2000 by Springer-Verlag New York Inc.
Subject
Life Sciences; Cell Biology; Anatomy; Zoology
ISSN
0938-8990
eISSN
1432-1777
D.O.I.
10.1007/s003350010176
Publisher site
See Article on Publisher Site

Abstract

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.

Journal

Mammalian GenomeSpringer Journals

Published: Feb 27, 2014

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