Analysis of a Quantitative Trait Locus for Seizure Susceptibility in Mice Using Bacterial Artificial Chromosome-Mediated Gene Transfer
Article first published online: 23 MAY 2007
© 2007 International League Against Epilepsy
Volume 48, Issue 9, pages 1667–1677, September 2007
How to Cite
Ferraro, T. N., Golden, G. T., Dahl, J. P., Smith, G. G., Schwebel, C. L., MacDonald, R., Lohoff, F. W., Berrettini, W. H. and Buono, R. J. (2007), Analysis of a Quantitative Trait Locus for Seizure Susceptibility in Mice Using Bacterial Artificial Chromosome-Mediated Gene Transfer. Epilepsia, 48: 1667–1677. doi: 10.1111/j.1528-1167.2007.01126.x
- Issue published online: 23 MAY 2007
- Article first published online: 23 MAY 2007
- Accepted February 19, 2007.
- Maximal electroshock seizure threshold;
Summary: Purpose: Previous quantitative trait loci (QTL) mapping studies from our laboratory identified a 6.6 Mb segment of distal chromosome 1 that contains a gene (or genes) having a strong influence on the difference in seizure susceptibility between C57BL/6 (B6) and DBA/2 (D2) mice. A gene transfer strategy involving a bacterial artificial chromosome (BAC) DNA construct that contains several candidate genes from the critical interval was used to test the hypothesis that a strain-specific variation in one (or more) of the genes is responsible for the QTL effect.
Methods: Fertilized oocytes from a seizure-sensitive congenic strain (B6.D2-Mtv7a/Ty-27d) were injected with BAC DNA and three independent founder lines of BAC-transgenic mice were generated. Seizure susceptibility was quantified by measuring maximal electroshock seizure threshold (MEST) in transgenic mice and nontransgenic littermates.
Results: Seizure testing documented significant MEST elevation in all three transgenic lines compared to littermate controls. Allele-specific RT-PCR analysis confirmed gene transcription from genome-integrated BAC DNA and copy-number-dependent phenotypic effects were observed.
Conclusions: Results of this study suggest that the gene(s) responsible for the major chromosome 1 seizure QTL is found on BAC RPCI23-157J4 and demonstrate the utility of in vivo gene transfer for studying quantitative trait genes in mice. Further characterization of this transgenic model will provide new insight into mechanisms of seizure susceptibility.