Szs1^DBA/2J
QTL Variant Detail

Summary

• QTL variant: Szs1^DBA/2J
• Name: seizure susceptibility 1; DBA/2J
• MGI ID: MGI:2154345
• QTL: Szs1 Location: Chr1:170878743-174456436 bp Genetic Position: Chr1, Syntenic

Variant origin

• Strain of Specimen: DBA/2J

Variant description

• Allele Type: QTL
• Mutation: Undefined
• This allele confers increased seizure susceptibility compared to C57BL/6J.
• Inheritance: Dominant

Notes

Szs1 is observed to interact with Szs2.

Candidate Genes

J:237163

In the current study, using reciprocal congenic strains B6.D2-Szs1 and D2.B6-Szs1 a comprehensive evaluation of the impact of allelic variation(s) within the QTL Szs1 on the inherited occurrence of the generalized non-convulsive spontaneous SWDs (spike and waves discharges) of D2 was carried out. A striking feature of the DBA/2J (D2) strain, not present in C57BL/6J (B6), is the frequent occurrence of high-amplitude, 6-8 hertz SWDs, which represents an endophenotype of thalamo-cortically generated SWDs typical of absence seizures, one of the most common forms of idiopathic generalized epilepsy (IGE). In all models of absence seizure, SWDs in D2 mice are associated with behavioral arrest.

Adult mice, 10-4 weeks of age, from each reciprocal congenic strain containing the Szs1 QTL, D2.B6-(D1Mit390-D1Mit17) and B6.D2-(D1Mit30-D1Mit17), were surgically prepared for EEG monitoring. EEG traces were analyzed by performing power spectrum with a fast Fourier algorithm using custom software written in Igor. Characteristics of SWD (duration, frequency and occurrence) were compared between strains using Mann-Whitney U test.

The results showed that congenic manipulation of the Szs1 locus drastically reduced the number and the duration of SWDs in D2.B6-Szs1 mice, however, it failed to induce the full expression of SWDs in B6.D2-Szs1. The results demonstrated that the occurrence of SWDs in D2 animals is under a polygenic control and therefore, the coupled D2 and B6 strains might be a useful model to dissect the genetic determinants of polygenic SWDs characteristic of typical absence seizures.

High resolution mapping of Szs1 showed that out of 120 genes in the introgressed congenic interval, 12 genes satisfy both criteria of being expressed in the brain and having a missense single nucleotide polymorphism (SNP). Among this latter group, one encodes a protein involved directly in the transport of ions across cell membranes: Kcnj10. This gene encodes an inward-rectifier potassium ion channel Kir4.1 predominantly expressed by glial cells. Homozygous Kcnj10 knockout mice show a severe demyelinating syndrome associated with multiple neurological defects including seizures and short life span.

The authors propose that changes in genes within or regulated by Szs1 such as Kcnj10 or Cacna1g, might account for the drastic decrease on SWDs occurrence in D2.B6-Szs1 mice when compared to D2 mice.

Mapping and Phenotype information for this QTL, its variants and associated markers

J:38888

In a population of F2 mice derived from B6D2F1 x B6D2F1 hybrids the quantitative trait locus seizure susceptibility 1 Szs1 was mapped to mouse Chromosome 1 within the D1Mit30 and D1Mit16 interval.

J:56630

DBA/2J and C57BL/6J mice exhibit differential sensitivity to seizure induced by pentylenetetrazol (PTZ) with DBA/2J mice being sensitive and C57BL/6J mice being relatively resistant. PTZ-induced seizure responses were studied in DBA/2J, C57BL/6J, (DBA/2Jx C57BL/6J)F1 and (DBA/2J x C57BL/6J)F2 intercross mice. QTL mapping and complementary statistical analysis identified loci on proximal (near D1Mit11) and distal (near D1Mit17) Chromosome 1. The peak LOD score on Chromosome 1 was associated with more distal markers D1Mit30 and D1Mit16 (LOD = 12.7 with 14.7% of total variance explained). The location of the peak coincides closely with the peak seen in a previously reported study (J:38888) of kainic acid-induced seizures in these strains of mice. The locus was assigned as Szs1. Candidate genes in this region include Atp1a2, Atp1b1 and Kcnj10. A second peak was detected more proximally, near markers D1Mit7 and D1Mit11 (LOD = 10.3 with 11.6% of total variance explained). This locus was designated as seizure susceptibility 5 (Szs5). A relevant candidate gene near this locus is Slc4a3. Both Szs1 and Szs5 are derived from DBA/2J-derived susceptibility alleles.

J:70295

A (C57BL/6J x DBA/2J)F2 intercross was used to map QTLs involved in seizure susceptibility in response to electroshock stimulus. DBA/2J exhibits a lower maximal electroshock seizure threshold (MEST) than C57BL/6J. F1 and F2 animals exhibit intermediate MEST values. Seizure susceptibility also appears to be a sex-influenced trait. C57BL/6J and F2 female animals have significantly lower MEST values than males. A major QTL was mapped to Chromosome 1 (79 cM) with a LOD score of 12.6 near D1Mit150. This QTL mapped to the same position as Szs1, a QTL for PZT-induced seizure susceptibility. Congenic strain B6.D2-Mtv7a/Ty(Mtv7) verified the Szs1 locus on Chromosome 1. B6.D2-Mtv7a/Ty(Mtv7) carries a small portion of DBA/2J-like DNA on chromosome 1, including D1Mit150, on a C57BL/6J background. The congenic exhibits similar MEST values and susceptibility to PZT-induced seizures as DBA/2J. Other major loci mapped to Chromosome 2 (Szs7) with a LOD of 3.7 spanning 1 cM - 15.3 cM, Chromosome 5 (Szs11) with a LOD of 6.8 spanning 8 cM - 39 cM, and Chromosome 15 (Szv3, a previously mapped QTL for kainic acid-induced seizure susceptibility) with a LOD of 5.0 spanning 6.7 cM - 22.2 cM. Szs13 also mapped to Chromosome 15 with LOD = 5.0 spanning 46.9 cM - 52.2 cM. Suggestiveloci were also identified: Szs8 (LOD = 2.9) on Chromosome 2 spanning 86 cM - 107cM, Szs9 (LOD = 2.9) on Chromosome 10 spanning 27 cM - 40 cM, Szs10 (LOD = 3.2) on Chromosome 11 spanning 20 cM - 34.25 cM, and Szs12 (LOD = 2.9) on Chromosome 13 spanning 45 cM - 59 cM.

J:89732

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).

References

• Original: J:70295 Ferraro TN, et al., Quantitative genetic study of maximal electroshock seizure threshold in mice: evidence for a major seizure susceptibility locus on distal chromosome 1. Genomics. 2001 Jul;75(1-3):35-42
• All: 4 reference(s)