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QTL Variant Detail
QTL variant: Gria4spkw1
Name: glutamate receptor, ionotropic, AMPA4 (alpha 4); spike wave discharge 1
MGI ID: MGI:3580141
Synonyms: Gria4IAP, Gria4spkw1-C3H/HeJ
QTL: Gria4  Location: Chr9:4417896-4796234 bp, - strand  Genetic Position: Chr9, 2.46 cM
Strain of Specimen:  C3H/HeJ
Allele Type:    QTL
Mutation:    Viral insertion
Mutation detailsThis mutation was originally identified as a QTL allele conferring increased incidence of spike wave discharges in the brains of C3H/HeJ mice as compared to C57BL/6J. Genomic PCR and sequencing showed a full-length intracisternal A-particle (IAP) proviral insertion in the last intron of Gria4 in C3H/HeJ mice. qRT-PCR showed a 10-fold difference in C3H/HeJ and C3HeB/FeJ substrains in transcripts detected between exons flanking the IAP-containing intron, and a neglible difference between upstream exon transcript levels in these substrains. Gria4 protein levels in C3H/HeJ cerebella are reduced compared with controls. (J:135814)
Inheritance:    Recessive
View phenotypes and curated references for all genotypes (concatenated display).
This allele interacts with spkw2. Animals with the highest incidence of spike wave discharges are homozygous for C3H/HeJ-derived alleles at spkw1 and heterozygous for C57BL/6J and C3H/HeJ alleles at spkw2.

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


678 male animals from a (C57BL/6J x DBA/2J)F2 intercross were used to map catalepsy-related QTLs. Markers were typed at an average density of 20 cM. Hpic1, a QTL for haloperidol-induced catalepsy, mapped to 48 cM (QTL range spanning 25 cM - 55 cM) on chromosome 9 with a LOD score of 5.4 at D9Mit111. Candidate genes found at this locus include Drd2, Ncam, Acat1, Htr1b, Chrna5, Myo5a, and El1. A probable QTL for halperidol-induced catalepsy, Hpic5, mapped to 9 cM on Chromosome 1 with a LOD score exceeding the threshold of 3.5 at D9Mit188 and D9Mit90. Potential candidate genes in this region are Penk-rs and Gria4. The dilute coat color was found to segregate against the parental phenotype. Dilute DBA/2J animals have a haloperidol ED50 of 0.4 mg/kg and dilute C57BL/6J animals have a haloperidol ED50 of 4.0 mg/kg.


Linkage analysis was performed on 53 animals from a (C3H/HeJ x C57BL/6J)F1 x C3H/HeJ backcross to identify QTLs associated with spike wave discharges (SWDs) in the cortex, thalamus, and hippocampus characteristic of absence seizures. Parental strain C3H/HeJ exhibits a high frequency of SWDs without associated brain abnormalities whereas parental strain C57BL/6J is SWD-negative. Over 120 SNPs at an average spacing of 20 markers were typed for the genome scan.

A significant locus accounting for over 40% of the SWD phenotypic variance mapped to centromeric mouse Chromosome 9. This locus is named spkw1 (spike wave 1) and the 95% confidence interval pans approximately 30 cM. C3H/HeJ-derived alleles at spkw1 confer increased SWD incidence and appear to have arecessive effect. Potential candidate genes mapping near spkw1 are Gria4 and Kcnj5. However, neither candidate gene exhibits sequence variation or differential expression between C3H/HeJ and C57BL/6J. The spkw1 locus is syntenic to a region of rat Chromosome 8 where suggestive association to absence seizures has been mapped.

Pairwise analysis revealed a modifying locus mouse Chromosome 8. This locus is named spkw2 (spike wave 2) and, together with spkw1, accounts for over 50% of the phenotypic variance in the backcross animals. C57BL/6J-derived alleles at spkw2 confer increased incidence of SWDs when in the presence of C3H/HeJ-derived spkw1 alleles.


Previously identified loci (chr 2, 9, and 10) associated with idiopathic generalized epilepsy were examined in (ABP/LeJ x EL/Suz)F2 animals to determine their effect in different environments. Parental strain EL/Suz is susceptible to spontaneous epileptic seizures whereas parental strain ABP/LeJ is non-epileptic. Seizure susceptibility appears to follow dominant inheritance after repeated testing in young or old mice, but appears to follow recessive inheritance in a single test in old mice. Animals were tested under 3 different environments. Environment 1 involved young animals (age 30 days) tested for seizures at four 30-day intervals, with the last test used for genotype analysis. Environment 2 involved old animals (age 150 days) tested once for seizures. Environment 3 involved old animals (age 150 days) tested for seizures at four 30-day intervals, with the last test used for genotype analysis.

Linkage to El4 (epilepsy 4) on mouse Chromosome 9 was detected in Environment 1 near D9Mit22 (LOD=4.35). This locus explained 20.1% of the variance and the QTL interval spanned D9Mit22 (28 cM) to D9Mit32 (35 cM). A novel locus named Elnv (epilepsy nave) was identified between D9Mit188 (9 cM) and D9Mit2 (17 cM) in Environment 2 with LOD=3.46. Elnv explained 9.2% of the variance. El4 and Elnv were also detected in Environment 3 (LOD=4.28 and LOD=6.29, respectively). El4 explained 12.7% of the variance, and Elnv explained 15.7% of the variance in Environment 3. Gria4 (8 cM) is a potential candidate gene for Elnv.

Linkage to El2 (epilepsy 2) on mouse Chromosome 2 was detected in Environment 1, but only in females. El2 mapped between D2Mit30 (69 cM) and D2Mit21 (80 cM) with LOD=3.72, and accounted for 35.2% of the variance.

Suggestive linkage to El3 (epilepsy 3)on mouse Chromosome 10 was detected in Environment 2 (LOD=2.29). El3 mapped between D10Mit42 and D10Mit134, and accounted for 5.6% of the variance.

Original:  J:98638 Frankel WN, et al., Development of a new genetic model for absence epilepsy: spike-wave seizures in C3H/He and backcross mice. J Neurosci. 2005 Mar 30;25(13):3452-8
All:  4 reference(s)

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