B6.129-Aldh5a1^tm1Kmg/J

Stock number: 006257
Research areas: Developmental Biology Research, Neurobiology Research, Research Tools

Description

Aldh5a1 knockout mice may be useful in studying succinate semialdehyde dehydrogenase (SSADH) deficiency and to explore the effect of GABA and GHB accumulation on central nervous system development and function.

Detailed description

Mice homozygous for the Aldh5a1 knockout exhibit reduced body weight, ataxia, seizures, gliosis of the hippocampus, and eventual status epilepticus. From 19-26 days of age, repetitive tonic-clonic seizures results in more than 95% mortality. Biochemical assays shows complete ablation of the endogenous enzymatic activity in the brains, livers, hearts, and kidneys of homozygous mutant mice. Homozygotes have increased levels of GHB and GABA in liver and brain tissues, as well as in urine. Phenotype can be rescued to varying degrees utilizing a number of both pharmacotherapeutic and gene therapeutic approaches. Although heterozygous mice have approximately 50% of the endogenous enzyme activity compared to wildtype mice, they are viable and fertile. Mice with this targeted mutation may be useful in studying succinate semialdehyde dehydrogenase (SSADH) deficiency and to explore the effect of GABA and GHB accumulation on central nervous system development and function.

Development

A targeting vector was designed to replace the 844 bp fragment (containing most of exon 7 and a large part of the active site) of the endogenous gene with a PGK-neo cassette. This construct was electroporated into "129/SV"-derived embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 blastocysts. Chimeric males were bred to C57BL/6 females. Heterozygous mice were backcrossed to C57BL/6 for at least ten generations prior to arrival at The Jackson Laboratory.

Allele

Symbol: Aldh5a1^tm1Kmg
Name: targeted mutation 1, K Michael Gibson
MGI accession ID: MGI:2180159
Generation method: Targeted
Attributes: Null/Knockout
Synonyms: Aldh5a1^-; SSADH^-; SSADH-deficient
Marker symbol: Aldh5a1
Marker name: aldhehyde dehydrogenase family 5, subfamily A1
Marker synonyms: 6330403E24Rik; D630032B01Rik; OTTMUSG00000000613; SSADH; SSDH
Chromosome: 13
Strain of origin: 129/Sv
Molecular note: A 1.65-kb neomycin cassette was used to replace 844 nucleotides comprising most of exon 7 and encoding the active site of the protein. Biochemical assays confirmed the ablation of enzymatic activity in the brains, livers, hearts, and kidneys of homozygous mutant mice.