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The subpopulation of CF-1 mice deficient in P-glycoprotein contains a murine retroviral insertion in the mdr1a gene

✍ Scribed by Todd R. Pippert; Diane R. Umbenhauer

Publisher
John Wiley and Sons
Year
2001
Tongue
English
Weight
201 KB
Volume
15
Category
Article
ISSN
1095-6670

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✦ Synopsis

Abstract

A subpopulation of the CF‐1 mouse strain is sensitive to neurotoxicity following exposure to avermectins, a family of structurally related antiparasitic agents. This unusual sensitivity is the result of a deficiency in the mdr1a P‐glycoprotein that normally contributes to a functional blood‐brain barrier. Previous studies demonstrated a correlation between P‐glycoprotein levels in the brain, intestine, testis, and placenta with an restriction fragment length polymorphism (RFLP) pattern from DNA isolated from the animals. We have demonstrated that only P‐glycoprotein derived from the mdr1a gene is deficient in these mice. In this article, we describe the genetic defect in the subpopulation of CF‐1 mice resulting in an absence of P‐glycoprotein. The data presented describes a reverse transcription–polymerase chain reaction (RT‐PCR) protocol that specifically amplifies mdr1a mRNA from tissue and confirms that the P‐glycoprotein defect results from a truncated mRNA with a deleted exon 23. Genomic amplification and sequencing of the intron between exon 22 and 23 in Pgp‐deficient animals reveals an insertion of approximately 8.35 kb of DNA at the exon 23 intron–exon junction corresponding to a murine leukemia virus. This insertion results in the aberrant splicing of the mRNA and the loss of exon 23 during RNA processing. © 2001 John Wiley & Sons, Inc. J Biochem Mol Toxicol 15:83–89, 2001

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