Szs11^DBA/2J
QTL Variant Detail

Summary

• QTL variant: Szs11^DBA/2J
• Name: seizure susceptibility 11; DBA/2J
• MGI ID: MGI:2155998
• QTL: Szs11 Location: unknown Genetic Position: Chr5, 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. (J:70295)
• Inheritance: Dominant

Notes

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

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. Suggestive loci were also identified: Szs8 (LOD = 2.9) on Chromosome 2 spanning 86 cM - 107 cM, 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:129499

Previously identified QTL Szs11 (seizure susceptibility 11) on mouse Chromosome 5 was confirmed and refined using congenic line analysis. A congenic line (B6.D2-Szs11) carrying the Szs11 locus derived from DBA/2J (seizure susceptible) on a C57BL/6J (seizure resistant) genetic background was constructed. The DBA/2J donor region spans markers D5Mit75 (20 cM) and D5Mit403 (61 cM). A reciprocal congenic line was constructed with a larger C57BL/6J donor segment, extending from D5Mit345 (centromere) to D5Mit403 (56 cM). Animals were tested daily to achieve maximal electroshock seizure threshold (MEST) beginning at 8-9 weeks of age.

Szs11 explained approximately 10% of the variance in congenic animals. Seizure resistance is conferred by C57BL/6J alleles at Szs11. As expected, D2.B6-Szs11 congenic animals displayed significantly higher MEST values compared to DBA/2J control animals. Conversely, B6.D2-Szs11 male congenic animals displayed lower MEST values (seizure susceptibility) compared to C57BL/6J control males. Seizure susceptibility did not differ significantly between B6.D2-Szs11 and C57BL/6J females.

Obvious candidate genes mapping to the Szs11 interval include Gabra2 (40 cM), Gabra4, Gabrb1, and Gabrg1 (40 cM). However, SNP analysis did not reveal polymorphism in gene sequences between C57BL/6J and DBA/2J. Differential gene expression analysis was not performed so it is unknown if the level of mRNA transcript differs between C57BL/6J and DBA/2J. Additional candidate genes for Szs11 are Slc34a2 (31 cM), Cckar (34 cM), Txk (40 cM), Chrna9 (41 cM), Cnga1 (41 cM), Gnrhr (44 cM), and Adrbk2 (60 cM).

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: 2 reference(s)