Article

Mammalian Genome

, Volume 15, Issue 4, pp 239-251

Fine mapping of a seizure susceptibility locus on mouse Chromosome 1: nomination of Kcnj10 as a causative gene

  • Thomas N. FerraroAffiliated withDepartment of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania 19104Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania 19104 Email author 
  • , Gregory T. GoldenAffiliated withDepartment of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania 19104Research Service, Veterans Affairs Medical Center, Coatesville, Pennsylvania 19320
  • , George G. SmithAffiliated withDepartment of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania 19104Research Service, Veterans Affairs Medical Center, Coatesville, Pennsylvania 19320
  • , James F. MartinAffiliated withDepartment of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania 19104Research Service, Veterans Affairs Medical Center, Coatesville, Pennsylvania 19320
  • , Falk W. LohoffAffiliated withDepartment of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania 19104
  • , Tracy A. GieringerAffiliated withDepartment of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania 19104
  • , Deborah ZamboniAffiliated withDepartment of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania 19104
  • , Candice L. SchwebelAffiliated withDepartment of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania 19104
  • , Danielle M. PressAffiliated withDepartment of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania 19104
    • , Stephanie Hongyu O. KratzerZhaoAffiliated withCenter for Biostatistics, Department of Epidemiology and Public Health, Yale University, New Haven, Connecticut 06510
    • , Wade H. BerrettiniAffiliated withDepartment of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania 19104Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania 19104
    • , Russell J. BuonoAffiliated withDepartment of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania 19104

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Abstract

Previous quantitative trait loci (QTL) mapping studies document that the distal region of mouse Chromosome (Chr) 1 contains a gene(s) that is in large part responsible for the difference in seizure susceptibility between C57BL/6 (B6) (relatively seizure-resistant) and DBA/2 (D2) (relatively seizure-sensitive) mice. We now confirm this seizure-related QTL (Szs1) using reciprocal, interval-specific congenic strains and map it to a 6.6-Mb segment between Pbx1 and D1Mit150. Haplotype conservation between strains within this segment suggests that Szs1 may be localized more precisely to a 4.1-Mb critical interval between Fcgr3 and D1Mit150. We compared the coding region sequences of candidate genes between B6 and D2 mice using RT-PCR, amplification from genomic DNA, and database searching and discovered 12 brain-expressed genes with SNPs that predict a protein amino acid variation. Of these, the most compelling seizure susceptibility candidate is Kcnj10. A survey of the Kcnj10 SNP among other inbred mouse strains revealed a significant effect on seizure sensitivity such that most strains possessing a haplotype containing the B6 variant of Kcnj10 have higher seizure thresholds than those strains possessing the D2 variant. The unique role of inward-rectifying potassium ion channels in membrane physiology coupled with previous strong association between ion channel gene mutations and seizure phenotypes puts even greater focus on Kcnj10 in the present model. In summary, we confirmed a seizure-related QTL of large effect on mouse Chr 1 and mapped it to a finely delimited region. The critical interval contains several candidate genes, one of which, Kcnj10, exhibits a potentially important polymorphism with regard to fundamental aspects of seizure susceptibility.