Mice heterozygous for the R43Q knockin to GABA A gamma2 receptor (Gabrg2) allele exhibit spontaneous behavioral arrest with spike and wave discharge (SWD). Homozygous mice do not survive beyond P19. These mice recapitulate the primary human seizure phenotype and may be useful for studying cortical inhibition and childhood absence epilepsy (CAE).
Steven Petrou, University of Melbourne
GABRG2 encodes the gamma 2 subunit of the GABA (gamma-aminobutyric acid) A receptor, a ligand-gated chloride channel involved in neuron inhibition. The amino acid substitution R43Q (arginine to glutamine) in GABRG2 is associated with febrile seizures (FS) and childhood absence epilepsy (CAE) in a large Australian family. Homozygous knockin mice with the R43Q amino acid substitution are born at less than the expected Mendelian ratio; survivors exhibit altered gaits, severe tremors and die by postnatal day 19. EEGs from homozygous mice indicate abnormal brain rhythms. Heterozygous mice on the C57BL/6 background exhibit spontaneous behavioral arrest with spike and wave discharge (SWD). On the DBA/2J background the seizure phenotype is more severe; SWDs are increased in number and duration. These GABA A gamma2(R43Q) mutant mice recapitulate the primary human seizure phenotype and maybe useful for studying cortical inhibition and childhood absence epilepsy.
A targeting vector containing the amino acid substitution arginine to glutamine at position 43 (R43Q), four silent mutations and a loxP flanked neomycin cassette was inserted into exon 2. The construct was electroporated into (129X1/SvJ x 129S1/Sv)F1-derived R1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts. The resulting chimeric animals were crossed to C57BL/6 mice for an unknown number of generations and then crossed to mice carrying Tg(CMV-cre)1Cgn to remove the neomycin cassette. GABA gamma2(R43Q) mice were backcrossed to C57BL/6 mice for at least 11 generations. Dr. Steve Petrou sent mice from his colony at the University of Melbourne to Dr. Wayne Frankel at The Jackson Laboratory. The strain was cryopreserved in 2010.
|Allele Name||targeted mutation 1, Steven Petrou|
|Allele Synonym(s)||Gabrg2R43Q; Gabrg2tmSpet; gamma2(R43Q)|
|Gene Symbol and Name||Gabrg2, gamma-aminobutyric acid (GABA) A receptor, subunit gamma 2|
|Strain of Origin||(129X1/SvJ x 129S1/Sv)F1-Kitl+|
|Molecular Note||The coding region was replaced with a coding region containing substitution that results in an amino acid substution of a glutamine for an arginine at position 43 (R43Q), 4 aditional silent mutations (not identified) and a floxed neo cassette that was subsequently removed by cre-mediated recombination. Expression levels were confirmed to be normal by RT-PCR analysis on total brain extracts. Reduction in protein product was confirmed by wesrtern blot analysis on extracts from E16 forebrains. This allele was generated from Gabrg2tm2Spet.|
While maintaining a live colony, these mice are bred as heterozygotes. Mice homozygous for the mutation die by P19.
When using the B6.129(Cg)-Gabrg2tm1Spet/Frk mouse strain in a publication, please cite the originating article(s) and include JAX stock #013209 in your Materials and Methods section.