Description

Strain Information

Type Congenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered Mutant Mice. Mating System +/+ sibling x Heterozygote         (Female x Male) Species laboratory mouse Generation N10+N2 (03-DEC-07)   Donating Investigator Michael Gibson,   Children's Hospital Pittsburgh

Description
Homozygous mutation of this gene results in 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 10 generations prior to arrival at The Jackson Laboratory.

Control Information

	Control
	Wild-type from the colony
	000664 C57BL/6J
Considerations for Choosing Controls

Additional Web Information

Congenic Nomenclature

Phenotype

Phenotype Information

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

The following phenotype information may relate to a genetic background differing from this JAX^® Mice strain.

Aldh5a1^tm1Kmg/Aldh5a1^tm1Kmg

        involves: 129/Sv * C57BL/6

• lethality-postnatal
• postnatal lethality (MGI Ref ID J:71949)
  • if untreated, homozygotes die of fatal seizures at day P16-P22
  • 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
  • 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
• behavior/neurological phenotype
• absence seizures (MGI Ref ID J:91856)
  • at P1-P16, unrestrained mutant neonates exhibit absence seizures identified by EEG analysis
• ataxia (MGI Ref ID J:71949)
  • homozygotes display truncal ataxia at ~P15-P18
• myoclonus (MGI Ref ID J:71949)
  • at ~P15-P18, homozygotes display spasms and myoclonic seizures, leading to status epilepticus and death
• tonic seizures (MGI Ref ID J:71949)
  • at about P15-P18, homozygotes display spasms and tonic seizures
• growth/size phenotype
• decreased body weight (MGI Ref ID J:71949)
  • homozygotes appear normal during the first days of life but display a 20-30% reduction in body weight relative to wild-type
• homeostasis/metabolism phenotype
• *normal* homeostasis/metabolism phenotype (MGI Ref ID J:75773)
  • homozygotes exhibit normal levels of Kreb's cycle intermediates in brain extracts, suggesting that global brain oxidative metabolism is unaffected
  • in mutant brain, the concentrations of glutamic acid and succinic acid are comparable to those of wild-type
• abnormal amino acid level (MGI Ref ID J:75773)
  • 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
  • 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
  • notably, glutamine levels are normal in mutant liver and kidney extracts
  • 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
• abnormal metabolism (MGI Ref ID J:71949)
  • 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 addition, homozygotes show elevated amounts of GHB and total GABA in homogenates of mutant kidney, pancreas and heart
• abnormal urine chemistry (MGI Ref ID J:71949)
  • homozygotes contain elevated amounts of gamma-hydroxybutyric (GHB) and total 4-aminobutyric acid (GABA) in urine
• muscle phenotype
• myoclonus (MGI Ref ID J:71949)
  • at ~P15-P18, homozygotes display spasms and myoclonic seizures, leading to status epilepticus and death
• renal/urinary system phenotype
• abnormal urine chemistry (MGI Ref ID J:71949)
  • homozygotes contain elevated amounts of gamma-hydroxybutyric (GHB) and total 4-aminobutyric acid (GABA) in urine
• nervous system phenotype
• abnormal brain wave pattern (MGI Ref ID J:91856)
  • at P1-P16, unrestrained mutant neonates exhibit absence seizures identified by EEG analysis
• absence seizures (MGI Ref ID J:91856)
  • at P1-P16, unrestrained mutant neonates exhibit absence seizures identified by EEG analysis
• gliosis (MGI Ref ID J:71949)
  • in homozygotes, preliminary data indicated astrogliosis of the hippocampus
• myoclonus (MGI Ref ID J:71949)
  • at ~P15-P18, homozygotes display spasms and myoclonic seizures, leading to status epilepticus and death
• tonic seizures (MGI Ref ID J:71949)
  • at about P15-P18, homozygotes display spasms and tonic seizures

View Research Applications

Research Applications

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

Developmental Biology Research
Growth Defects Growth Defects (homozygous)
Internal/Organ Defects (brain)

Neurobiology Research
Ataxia (Movement) Defects
Behavioral and Learning Defects
Epilepsy
Neurotransmitter Receptor and Synaptic Vesicle Defects

Research Tools
Cell Biology Research
Developmental Biology Research

Genes & Alleles

Gene & Allele Information

Allele Symbol		Aldh5a1tm1Kmg
Allele Name		targeted mutation 1, K Michael Gibson
Allele Type		Targeted (knock-out)
Common Name(s)		Aldh5a1-; SSADH-deficient; SSADH-;
Mutation Made By		Michael Gibson,   Children's Hospital Pittsburgh
Strain of Origin		129/Sv
Gene Symbol and Name		Aldh5a1, aldhehyde dehydrogenase family 5, subfamily A1
Chromosome		13
Gene Common Name(s)		D630032B01Rik; RIKEN cDNA D630032B01 gene; SSADH; SSDH;
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. [MGI Ref ID J:71949]

Genotyping

Genotyping Information

Genotyping Protocols

Aldh5a1^tm1Kmg, SEP PCR, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

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):212-6. [PubMed: 11544478]  [MGI Ref ID J:71949]

Additional References

Aldh5a1^tm1Kmg related

Barcelo-Coblijn G; Murphy EJ; Mills K; Winchester B; Jakobs C; Snead OC rd; Gibson KM. 2007. Lipid abnormalities in succinate semialdehyde dehydrogenase (Aldh5a1-/-) deficient mouse brain provide additional evidence for myelin alterations. Biochim Biophys Acta 1772(5):556-62. [PubMed: 17300923]  [MGI Ref ID J:121643]

Buzzi A; Wu Y; Frantseva MV; Perez Velazquez JL; Cortez MA; Liu CC; Shen LQ; Gibson KM; Snead OC rd. 2006. Succinic Semialdehyde Dehydrogenase Deficiency: GABA(B) receptor-mediated function. Brain Res 1090(1):15-22. [PubMed: 16647690]  [MGI Ref ID J:109671]

Chowdhury GM; Gupta M; Gibson KM; Patel AB; Behar KL. 2007. Altered cerebral glucose and acetate metabolism in succinic semialdehyde dehydrogenase-deficient mice: evidence for glial dysfunction and reduced glutamate/glutamine cycling. J Neurochem 103(5):2077-91. [PubMed: 17854388]  [MGI Ref ID J:128716]

Cortez MA; Wu Y; Gibson KM; Snead OC rd. 2004. Absence seizures in succinic semialdehyde dehydrogenase deficient mice: a model of juvenile absence epilepsy. Pharmacol Biochem Behav 79(3):547-53. [PubMed: 15582027]  [MGI Ref ID J:102295]

Gibson KM; Schor DS; Gupta M; Guerand WS; Senephansiri H; Burlingame TG; Bartels H; Hogema BM; Bottiglieri T; Froestl W; Snead OC; Grompe M; Jakobs C. 2002. Focal neurometabolic alterations in mice deficient for succinate semialdehyde dehydrogenase. J Neurochem 81(1):71-9. [PubMed: 12067239]  [MGI Ref ID J:75773]

Gupta M; Greven R; Jansen EE; Jakobs C; Hogema BM; Froestl W; Snead OC; Bartels H; Grompe M; Gibson KM. 2002. Therapeutic intervention in mice deficient for succinate semialdehyde dehydrogenase (gamma-hydroxybutyric aciduria). J Pharmacol Exp Ther 302(1):180-7. [PubMed: 12065715]  [MGI Ref ID J:125589]

Gupta M; Hogema BM; Grompe M; Bottiglieri TG; Concas A; Biggio G; Sogliano C; Rigamonti AE; Pearl PL; Snead OC rd; Jakobs C; Gibson KM. 2003. Murine succinate semialdehyde dehydrogenase deficiency. Ann Neurol 54 Suppl 6:S81-90. [PubMed: 12891658]  [MGI Ref ID J:115678]

Gupta M; Polinsky M; Senephansiri H; Snead OC; Jansen EE; Jakobs C; Gibson KM. 2004. Seizure evolution and amino acid imbalances in murine succinate semialdehyde dehydrogenase (SSADH) deficiency. Neurobiol Dis 16(3):556-62. [PubMed: 15262267]  [MGI Ref ID J:91856]

Jansen EE; Verhoeven NM; Jakobs C; Schulze A; Senephansiri H; Gupta M; Snead OC; Gibson KM. 2006. Increased guanidino species in murine and human succinate semialdehyde dehydrogenase (SSADH) deficiency. Biochim Biophys Acta 1762(4):494-8. [PubMed: 16504488]  [MGI Ref ID J:110214]

Mehta AK; Gould GG; Gupta M; Carter LP; Gibson KM; Ticku MK. 2006. Succinate semialdehyde dehydrogenase deficiency does not down-regulate gamma-hydroxybutyric acid binding sites in the mouse brain. Mol Genet Metab 88(1):86-9. [PubMed: 16406647]  [MGI Ref ID J:108196]

Sauer SW; Kolker S; Hoffmann GF; Ten Brink HJ; Jakobs C; Gibson KM; Okun JG. 2007. Enzymatic and metabolic evidence for a region specific mitochondrial dysfunction in brains of murine succinic semialdehyde dehydrogenase deficiency (Aldh5a1-/- mice). Neurochem Int 50(4):653-9. [PubMed: 17303287]  [MGI Ref ID J:124486]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX11

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, heterozygous mice are bred. Homozygous mice will die around three weeks of age with seizures.
Mating System	+/+ sibling x Heterozygote         (Female x Male)
Diet Information	LabDiet® 5K52/5K67

Purchasing information

Pricing, Supply Level & Notes, Controls, General Terms & Conditions

Pricing

Supply Details

Standard Supply

Repository-Live. A collection of over 1000 strains maintained as live colonies. Individual colonies are sized to meet current customer demand. Delivery for orders of 10 mice or less ranges on average from one to eight weeks; mice are generally shipped between four to six weeks of age with a maximum shipping age of ~nine weeks. Colony sizes do not generally support stringent age specifications for large volumes of mice; however custom orders and larger quantities of mice are easily arranged. Estimated ship dates for all orders provided within 48 hours of order placement.

Supply Notes

Usually shipped between four and eight weeks of age. This strain is included in the Induced Mutant Resource Colony collection.

Control Information

	Control
	Wild-type from the colony
	000664 C57BL/6J
Considerations for Choosing Controls
USA, Canada and Mexico - Control Pricing Information for Genetically Engineered Mutant Strains.
International - Control Pricing Information for Genetically Engineered Mutant Strains.

General Terms and Conditions

See Terms of Use

The Jackson Laboratory's Genotype Promise

The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX^® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX^® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX^® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project.

---

Ordering and Purchasing Information

      Purchasing Information
      JAX^® Mice Orders
      Surgical Services

Contact Information
Orders & Technical Support
Tel: 800.422.6423 or 207.288.5845
Fax: 207.288.6150
Technical Support Email Form

Terms of Use

Terms of Use

General Terms and Conditions

Contact information

General inquiries

Contracts Administration

phone:	207-288-6470
fax:	207-288-6655

JAX^® Mice & Services Conditions of Use

“Each recipient institution, including its employees and other researchers under its control (RECIPIENT), of mice or services using mice from The Jackson Laboratory (TJL) agrees that such mice, descendants of those mice derived by inbreeding or crossbreeding, including unmodified derivatives of those mice or their descendants (“MICE”) shall not be: (i) used for any purpose other than the internal research of the RECIPIENT, (ii) sold or otherwise provided to any third party for any use, or (iii) provided to any agent or other third party to provide breeding or other services with respect to MICE. Acceptance of MICE from TJL shall be deemed agreement by RECIPIENT to these conditions, and departure from these conditions requires The Jackson Laboratory’s prior written authorization.”

In case of dissatisfaction for a valid reason and claimed in writing by a purchaser within ninety (90) days of receipt of MICE, products or services, The Jackson Laboratory will, at its option, provide credit or replacement for the MICE or product received or the services provided.

No Liability

In no event shall The Jackson Laboratory, its trustees, directors, officers, employees, and affiliates be liable for any causes of action or damages, including any direct, indirect, special, or consequential damages, arising out of the provision of MICE, products or services, including economic damage or injury to property and lost profits, and including any damage arising from acts or negligence on the part of The Jackson Laboratory, its agents or employees. In purchasing or receiving MICE, products or services from The Jackson Laboratory, purchaser or recipient, or any party claiming by or through them, expressly releases and discharges The Jackson Laboratory from all such causes of action or damages, and further agrees to defend and indemnify The Jackson Laboratory from any costs or damages arising out of any third party claims.

MICE and biological materials are to be used in a safe manner and in accordance with all applicable governmental rules and regulations.

The foregoing represents the General Terms and Conditions applicable to The Jackson Laboratory’s MICE, products and services. In addition, special terms and conditions of sale of certain MICE, products and services may be set forth separately in The Jackson Laboratory web pages, catalogs, price lists, contracts, and/or other documents, and these special terms and conditions shall also govern the sale of these MICE, products and services by The Jackson Laboratory, and by its licensees and distributors.

Acceptance of delivery of MICE, products or services shall be deemed agreement to these terms and conditions. No purchase order or other document transmitted by purchaser or recipient that may modify the terms and conditions hereof, shall be in any way binding on The Jackson Laboratory, and instead the terms and conditions set forth herein, including any special terms and conditions set forth separately, shall govern the sale of MICE, products services by The Jackson Laboratory.