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

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Ivermectin neurotoxicity in a CF-1 mouse subpopulation is linked to mdr-3 P-glycoprotein deficiency.
• Understanding the genetic basis of this deficiency is crucial for studying drug responses and gene regulation.

Purpose of the Study:

• To characterize the molecular mutation in the mdr-3 gene responsible for ivermectin sensitivity in CF-1 mice.
• To investigate the mechanism by which this mutation leads to neurotoxicity.

Main Methods:

• Reverse transcription-polymerase chain reaction (RT-PCR) for mRNA analysis.
• DNA sequencing of RT-PCR products and genomic DNA.
• Histopathological examination of mouse brains.

Main Results:

• A deletion or alteration in exon 23 of the mdr-3 gene was identified in mutant mice.
• An insertion of a solo ecotropic murine leukemia virus long terminal repeat (LTR) in the mdr-3 intron was found, causing aberrant splicing.
• Ivermectin treatment of mutants resulted in selective neuronal degeneration in the hippocampal CA3 region.

Conclusions:

• This study reports the first instance of a gene mutation induced by a solo retroviral LTR with a resulting phenotype in mice.
• The findings offer new insights into how viral solo LTRs can impact mammalian gene expression and cause neurotoxicity.