Experiment
The seizure susceptibility locus Szs1 (at 79 cM on mouse Chromosome 1) was refined to a 4.1 Mb interval using interval specific congenic strains (ICSC) and haplotype analysis. Four ICSC were derived from crossing donor strain congenic B6.D2-Mtv-7a/Ty to background strain C57BL/6J. (B6.D2-Mtv-7a/Ty carries a small portion of DBA/2J-like DNA on chromosome 1, including D1Mit150 near Szs1, on a C57BL/6J background.) Parental strain DBA/2J exhibits a lower maximal electroshock seizure threshold (MEST) than C57BL/6J. ISCS animals inheriting DBA/2J-derived DNA between Pbx1 (88 cM) and D1Mit150 (100 cM) exhibit lower MEST values compared to animals inheriting DBA/2J-derived DNA distal to D1Mit150. Haplotype analysis further localized Szs1 to an interval between Fcgr3 (92.3 cM) and D1Mit150 (100 cM).
Approximately 100 genes map to the refined Szs1 interval, four of which are involved in the transport of ions across cell membranes. These genes are Atp1a2 (94.2 cM), Atp1a4 (94 cM), Kcnj9 (94.2 cM), and Kcnj10 (93.5 cM). Of particular interest is Kcnj10- this gene is expressed in the brain and contains an SNP between C57BL/6J and DBA/2J resulting in an amino acid change (Thr26Ser). Seizure resistant strain C57BL/6J carries the thr26 allele at Kcnj10 while seizure susceptible strain DBA/2J carries the ser26 allele. Most strains with thr26 (C57BL/6J, C57L, C57BL/6ByJ, C57BL/10J, C57BL/10SnJ) exhibit higher seizure thresholds compared to strains carrying ser26 (DBA/2J, 129/SvImJ, AKR/J, SWR/J, BALB/cJ, C3H/HeJ, Ei/Suz).
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