Overview

This strain is currently unavailable due to replenishing of cryopreserved stocks. Interested customers can register interest.

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.

Donating Investigator

Michael Gibson, Children's Hospital Pittsburgh

Genetic overview

Genetic Background	Generation

Aldh5a1^tm1Kmg

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Aldh5a1	aldhehyde dehydrogenase family 5, subfamily A1

View Genetics

Research Applications

Neurobiology Research
Developmental Biology Research
Research Tools

View All Research Applications

Details

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.

Control Suggestions

Wild-type from the colony
000664 C57BL/6J

Additional Information

Considerations for Choosing Controls

Selected References

Hogema BM; Gupta M; Senephansiri H; Burlingame TG; Taylor M; Jakobs C; Schutgens RB; Froestl W; Snead OC; Diaz-Arrastia R; Bottiglieri T; Grompe M; Gibson KM. 2001. Pharmacologic rescue of lethal seizures in mice deficient in succinate semialdehyde dehydrogenase. Nat Genet 29(2):212-6PubMed: 11544478 MGI: J:71949

View All References

Genetics

Aldh5a1^tm1Kmg

Allele Symbol: Aldh5a1^tm1Kmg

Allele Name	targeted mutation 1, K Michael Gibson
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	Aldh5a1^-; SSADH^-; SSADH-deficient
Gene Symbol and Name	Aldh5a1, aldhehyde dehydrogenase family 5, subfamily A1
Gene Synonym(s)
Strain of Origin	129/Sv
Chromosome	13
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.
Mutations Made By	Michael Gibson, Children's Hospital Pittsburgh

Disease/Phenotype

Disease Terms

Models with phenotypic similarity to human diseases where etiology is unknown or involving genes where ortholog is unknown.

epilepsy

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Neurobiology Research
- Epilepsy
- Neurotransmitter Receptor and Synaptic Vesicle Defects
- Behavioral and Learning Defects
- Ataxia (Movement) Defects
Developmental Biology Research
- Internal/Organ Defects
  - brain
- Growth Defects
  - Growth Defects (homozygous)
Research Tools
- Cell Biology Research
- Developmental Biology Research

Mammalian Phenotype Terms by Genotype

The following phenotype information is associated with a similar, but not exact match to this JAX^® Mice strain

Genotype: Aldh5a1^tm1Kmg/Aldh5a1^tm1Kmg
involves: 129/Sv * C57BL/6

homeostasis/metabolism phenotype

decreased glutamine level
- in brain extracts, P0-P18 homozygotes show low glutamine both before and after the period of lethal tonic-clonic seizures
- homozygotes show a significant reduction of glutamine in mutant brain homogenates, despite normal glutamine synthetase protein and mRNA levels
- in brain, glutamine depletion is detected in the frontal cortex, parietal cortex, hippocampus and cerebellum
- Normal - however, glutamine levels are normal in mutant liver and kidney extracts

increased beta-alanine level
- homozygotes exhibit normal levels of total beta-alanine in urine and total homogenates of mutant brain, heart and pancreas, but elevated concentrations in kidney and liver homogenates

increased gamma-aminobutyric acid level
- homozygotes show elevated amounts of GHB and total GABA in homogenates of mutant kidney, pancreas and heart
- in brain extracts, P0-P18 homozygotes show high GABA/low glutamine both before and after the period of lethal tonic-clonic seizures
- in mutant liver and brain homogenates, the amounts of GHB and total GABA are increased 30-45 and 2.5-3 fold, respectively, relative to wild-type

abnormal amino acid level
- in brain extracts, P0-P18 homozygotes show high GABA/low glutamine both before and after the period of lethal tonic-clonic seizures
- brain homogenates show additional amino acid neurotransmitter abnormalities which may temporally correlate with the onset of lethal convulsions

increased urine gamma-aminobutyric acid level
- homozygotes contain elevated amounts of gamma-hydroxybutyric (GHB) and total 4-aminobutyric acid (GABA) in urine

mammalian phenotype

homeostasis/metabolism phenotype
- Normal - homozygotes exhibit normal levels of Kreb's cycle intermediates in brain extracts, suggesting that global brain oxidative metabolism is unaffected
- Normal - in mutant brain, the concentrations of glutamic acid and succinic acid are comparable to those of wild-type

behavior/neurological phenotype

ataxia
- homozygotes display truncal ataxia at ~P15-P18

myoclonus
- at ~P15-P18, homozygotes display spasms and myoclonic seizures, leading to status epilepticus and death

absence seizures
- at P1-P16, unrestrained mutant neonates exhibit absence seizures identified by EEG analysis

tonic seizures
- at about P15-P18, homozygotes display spasms and tonic seizures

mortality/aging

postnatal lethality, complete penetrance
- if untreated, homozygotes die of fatal seizures at day P16-P22
- administration of taurine, which is derived from the metabolism of cysteine and is highly present in mother's milk, via drinking water (up to 5,000 mg/kg/d) provides rescue through the critical period
- therapeutic intervention with anticonvulsants phenobarbital or phenytoin fails to ameliorate survival
- in contrast, intervention with vigabatrin or the GABAB receptor antagonist CGP 35348 prevents tonic-clonic convulsions and prolongs survival

muscle phenotype

myoclonus
- at ~P15-P18, homozygotes display spasms and myoclonic seizures, leading to status epilepticus and death

nervous system phenotype

increased beta-alanine level
- homozygotes exhibit normal levels of total beta-alanine in urine and total homogenates of mutant brain, heart and pancreas, but elevated concentrations in kidney and liver homogenates

myoclonus
- at ~P15-P18, homozygotes display spasms and myoclonic seizures, leading to status epilepticus and death

abnormal brain wave pattern
- at P1-P16, unrestrained mutant neonates exhibit absence seizures identified by EEG analysis

absence seizures
- at P1-P16, unrestrained mutant neonates exhibit absence seizures identified by EEG analysis

gliosis
- in homozygotes, preliminary data indicated astrogliosis of the hippocampus

increased gamma-aminobutyric acid level
- in mutant liver and brain homogenates, the amounts of GHB and total GABA are increased 30-45 and 2.5-3 fold, respectively, relative to wild-type
- in brain extracts, P0-P18 homozygotes show high GABA/low glutamine both before and after the period of lethal tonic-clonic seizures
- homozygotes show elevated amounts of GHB and total GABA in homogenates of mutant kidney, pancreas and heart

tonic seizures
- at about P15-P18, homozygotes display spasms and tonic seizures

increased urine gamma-aminobutyric acid level
- homozygotes contain elevated amounts of gamma-hydroxybutyric (GHB) and total 4-aminobutyric acid (GABA) in urine

renal/urinary system phenotype

increased urine gamma-aminobutyric acid level
- homozygotes contain elevated amounts of gamma-hydroxybutyric (GHB) and total 4-aminobutyric acid (GABA) in urine

growth/size/body region phenotype

decreased body weight
- homozygotes appear normal during the first days of life but display a 20-30% reduction in body weight relative to wild-type

References

Hogema BM; Gupta M; Senephansiri H; Burlingame TG; Taylor M; Jakobs C; Schutgens RB; Froestl W; Snead OC; Diaz-Arrastia R; Bottiglieri T; Grompe M; Gibson KM. 2001. Pharmacologic rescue of lethal seizures in mice deficient in succinate semialdehyde dehydrogenase. Nat Genet 29(2):212-6PubMed: 11544478 MGI: J:71949

Additional - Aldh5a1^tm1Kmg related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Standard PCR:Aldh5a1
- Separated PCR:Aldh5a1
- Genotyping resources and troubleshooting
Breeding Considerations

When maintaining a live colony, heterozygous mice are bred. Homozygous mice will die around three weeks of age with seizures.
- Additional Breeding and Husbandry Support
Citation
When using the B6.129-Aldh5a1^tm1Kmg/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #006257 in your Materials and Methods section.

Strain Interest Registration

Please fill out the form below to indicate your interest in purchasing this JAX®Mice strain.
This information helps us manage the colony build and better meet the broad needs of the research community.
Please send any technical questions to Technical Support.

Contact Information

First Name

First name is required

Last Name

Last name is required

Institution

Institution is Required

Phone Number

Phone Number is required

Email

Email is required

Interest

Please indicate your approximate levels of interest. You can add another line by selecting "Add More Interest".

Number of Mice

Frequency

Product

Comment

Terms Of Use

General Terms and Conditions

Questions about Terms of Use

Licensing Information

Phone: 207-288-6470

Email: TechTran@jax.org

Donating Investigator

Genetic overview

Research Applications

Detailed Description

Development

Control Suggestions

Additional Information

Selected References

Aldh5a1tm1Kmg

Allele Symbol: Aldh5a1tm1Kmg

Disease Terms

Models with phenotypic similarity to human diseases where etiology is unknown or involving genes where ortholog is unknown.

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Mammalian Phenotype Terms by Genotype

Genotype: Aldh5a1tm1Kmg/Aldh5a1tm1Kmginvolves: 129/Sv * C57BL/6

homeostasis/metabolism phenotype

mammalian phenotype

behavior/neurological phenotype

mortality/aging

muscle phenotype

nervous system phenotype

renal/urinary system phenotype

growth/size/body region phenotype

References

Additional - Aldh5a1tm1Kmg related

Genotyping Protocols

Breeding Considerations

Citation

Strain Interest Registration

Contact Information

Interest

Terms Of Use

Licensing Information

Aldh5a1^tm1Kmg

Allele Symbol: Aldh5a1^tm1Kmg

Genotype: Aldh5a1^tm1Kmg/Aldh5a1^tm1Kmg
involves: 129/Sv * C57BL/6

Additional - Aldh5a1^tm1Kmg related