Overview

This Lias^tm1Mae mutant allele has the exons 4-6 of the of the lipoic acid synthetase (Lias) gene deleted. The deleted region encodes the functionally conserved Cys motifs of the enzyme responsible for converting octanoic acid to α-lipoic acid (also called 1,2-dithiolane-3-pentanoic acid, thioctic acid, ALA, or LA). These Lias mutant mice may be useful in studying α-lipoic acid requirements during development, mitochondrial dysfunction, and oxidative stress-related diseases such as diabetes, atherosclerosis, and neurodegenerative disorders.

Donating Investigator

Dr. Nobuyo Maeda, University of North Carolina at Chapel Hill

Genetic overview

Genetic Background	Generation

Lias^tm1Mae

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Lias	lipoic acid synthetase

View Genetics

Research Applications

Cardiovascular Research
Metabolism Research
Research Tools
Diabetes and Obesity Research
Developmental Biology Research
Immunology, Inflammation and Autoimmunity Research
Neurobiology Research

View All Research Applications

Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

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Details

Detailed Description

The Lias^tm1Mae mutant allele has the exons 4-6 of the of the lipoic acid synthetase (Lias) gene deleted. The deleted region encodes the functionally conserved Cys motifs of the enzyme responsible for converting octanoic acid to α-lipoic acid (also called 1,2-dithiolane-3-pentanoic acid, thioctic acid, ALA, or LA) via insertion of a sulfur atom into the hydrocarbon chain of octanoic acid. Lias mRNA expression in heterozygous mice is approximately half of wildtype levels. Lias homozygous mice die in utero shortly after implantation. When heterozygous dams are fed an exogenous racemic α-lipoic acid diet (equal amounts of left- and right-handed enantiomers of the chiral α-lipoic acid molecule), embryonic lethality of homozygous embryos is not rescued. Heterozygous mice are viable and fertile, with a mild reduction of plasma antioxidant capacity. Inducing stress conditions (such as inflammation, hypercholesterolemia and hyperglycemia) is expected to result in significantly reduced endogenous antioxidant capacity. Specifically, heterozygous mice exhibit significantly increased reactive oxygen species (ROS) levels following lipopolysaccharide-induced sepsis. In addition, heterozygous Lias-deficiency enhances atherosclerosis in apoE-deficient male mice (see details below). These Lias mutant mice may be useful in studying α-lipoic acid requirements during development, mitochondrial dysfunction, and oxidative stress-related diseases such as diabetes, atherosclerosis, and neurodegenerative disorders.

When 129S6-Lias mutant mice are bred with 129S6-apoE mutant mice
(Stock No. 014556), enhanced atherosclerosis and reduced antioxidant capacity is observed in males heterozygous for the Lias mutation and homozygous for the apoE mutation (129S6-Lias^+/-apoE^-/-). Compared to 129S6-apoE^-/- males, 129S6-Lias^+/-apoE^-/- males have significantly larger atherosclerotic lesions at the aortic sinus accompanied by enhanced oxidative stress, increased plasma cholesterol, and a transition from glucose to lipid catabolism in the liver (reduced pyruvate dehydrogenase complex activity). 129S6-Lias^+/-apoE^-/- males have significant reductions in aortic expression of antioxidant enzyme genes (including superoxide dismutase 1 and 2 (SOD1 and SOD2)) compared to 129S6-apoE^-/- males.

Development

A targeting vector was designed in the laboratory of Dr. Nobuyo Maeda (University of North Carolina at Chapel Hill) to replace exons 4-6 of the lipoic acid synthetase (Lias) gene with a reverse-oriented neomycin resistance cassette. The deleted ~3.7 kbp region encodes the functionally conserved Cys motifs of the enzyme responsible for converting octanoic acid to α-lipoic acid (also called 1,2-dithiolane-3-pentanoic acid, thioctic acid, ALA, or LA) via insertion of a sulfur atom into the hydrocarbon chain of octanoic acid. To generate mutant mice on a 129S6/SvEv genetic background, the construct was electroporated into 129S6/SvEvTac-derived W4 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts and chimeric males were bred with 129S6/SvEvTac females to establish the colony. Mice heterozygous for the Lias^tm1Mae mutant allele were maintained on a 129S6/SvEvTac genetic background prior to sending to The Jackson Laboratory Repository. Upon arrival, mutant mice were maintained on the 129S6/SvEvTac genetic background by breeding heterozygous mice with wildtype mice from the colony.

Selected References

Yi X; Kim K; Yuan W; Xu L; Kim HS; Homeister JW; Key NS; Maeda N. 2009. Mice with heterozygous deficiency of lipoic acid synthase have an increased sensitivity to lipopolysaccharide-induced tissue injury. J Leukoc Biol 85(1):146-53PubMed: 18845616 MGI: J:143405
Yi X; Maeda N. 2005. Endogenous production of lipoic acid is essential for mouse development. Mol Cell Biol 25(18):8387-92PubMed: 16135825 MGI: J:101368
Yi X; Xu L; Kim K; Kim HS; Maeda N. 2010. Genetic reduction of lipoic acid synthase expression modestly increases atherosclerosis in male, but not in female, apolipoprotein E-deficient mice. Atherosclerosis 211(2):424-30PubMed: 20347443 MGI: J:174991

View All References

Genetics

Lias^tm1Mae

Allele Symbol: Lias^tm1Mae

Allele Name	targeted mutation 1, Nobuyo Maeda
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	Lias^-
Gene Symbol and Name	Lias, lipoic acid synthetase
Gene Synonym(s)
Strain of Origin	129S6/SvEvTac
Chromosome	5
Molecular Note	A 3.7 kb sequence including exons 4-6 was replaced by a neomycin resistance gene. The deleted sequence encoded the functionally conserved Cys motifs, and loss of it resulted in a null allele.
Mutations Made By	Dr. Nobuyo Maeda, University of North Carolina at Chapel Hill

Disease/Phenotype

Disease Terms

Research Areas By Phenotype

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

Cardiovascular Research
- Other
  - altered fat metabolism
  - altered lipoprotein profile
- Atherosclerosis
- Hypertriglyceridemia
- Hypercholesterolemia
- Vascular Defects
- Diet-Induced Atherosclerosis
- Heart Abnormalities
Metabolism Research
- Lipid Metabolism
- Free Radical Research
- Enzyme Deficiency
Research Tools
- Cardiovascular Research
- Diabetes and Obesity Research
- Metabolism Research
- Neurobiology Research
- Immunology, Inflammation and Autoimmunity Research
- Toxicology Research
  - free radical research
Diabetes and Obesity Research
- Type 2 Diabetes (NIDDM)
- Obesity Without Diabetes
  - diet-induced
Developmental Biology Research
- Embryonic Lethality (Homozygous)
Immunology, Inflammation and Autoimmunity Research
- Inflammation
Neurobiology Research
- Behavioral and Learning Defects
- Neurodegeneration

Mammalian Phenotype Terms by Genotype

The following phenotype relates to a compound genotype created using this strain

Genotype: Lias^tm1Mae/Lias^tm1Mae
either: 129S6/SvEvTac-Lias or (involves: 129S6/SvEvTac * C57BL/6J)

embryo phenotype

decreased embryo size
- embryos are smaller at E7.5

embryonic growth arrest
- embryos appear to stop growing at the egg cylinder stage

growth/size/body region phenotype

decreased embryo size
- embryos are smaller at E7.5

mortality/aging

embryonic lethality between somite formation and embryo turning, complete penetrance
- even with lipoic acid supplementation of the dams no live born homozygotes are found
- homozygous embryos die between E7.5 and E9.5

Genotype: Lias^tm1Mae/Lias⁺
either: 129S6/SvEvTac-Lias or (involves: 129S6/SvEvTac * C57BL/6J)

homeostasis/metabolism phenotype

decreased glutathione level
- levels of glutathione in erythrocytes are significantly reduced; however plasma glucose, triglyceride, and cholesterol levels are normal and no increase in thiobarbituric acid-reactive substances (TBARS, a measure of oxidative stress) is seen

References

Yi X; Kim K; Yuan W; Xu L; Kim HS; Homeister JW; Key NS; Maeda N. 2009. Mice with heterozygous deficiency of lipoic acid synthase have an increased sensitivity to lipopolysaccharide-induced tissue injury. J Leukoc Biol 85(1):146-53PubMed: 18845616 MGI: J:143405
Yi X; Maeda N. 2005. Endogenous production of lipoic acid is essential for mouse development. Mol Cell Biol 25(18):8387-92PubMed: 16135825 MGI: J:101368
Yi X; Xu L; Kim K; Kim HS; Maeda N. 2010. Genetic reduction of lipoic acid synthase expression modestly increases atherosclerosis in male, but not in female, apolipoprotein E-deficient mice. Atherosclerosis 211(2):424-30PubMed: 20347443 MGI: J:174991

Additional - Lias^tm1Mae related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Genotyping resources and troubleshooting
Breeding Considerations

When maintaining a live colony, heterozygous mice may be bred together or to wildtype mice from the colony. Homozygous knockout mice die in utero shortly after implantation.
- Additional Breeding and Husbandry Support
Citation
When using the 129S6/SvEv-Lias^tm1Mae/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #013046 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Pricing & Availability

Cryo Recovery

Domestic
International

Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Pricing

Service/Product	Description	Price
	Heterozygous or wildtype for Lias<tm1Mae>

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Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Selected References

Liastm1Mae

Allele Symbol: Liastm1Mae

Disease Terms

Research Areas By Phenotype

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

Mammalian Phenotype Terms by Genotype

Genotype: Liastm1Mae/Liastm1Maeeither: 129S6/SvEvTac-Lias or (involves: 129S6/SvEvTac * C57BL/6J)

embryo phenotype

growth/size/body region phenotype

mortality/aging

Genotype: Liastm1Mae/Lias+either: 129S6/SvEvTac-Lias or (involves: 129S6/SvEvTac * C57BL/6J)

homeostasis/metabolism phenotype

References

Additional - Liastm1Mae related

Genotyping Protocols

Breeding Considerations

Citation

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Live Mouse

Cryorecovery - Pricing

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms Of Use

Additional Use Restrictions Apply

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Lias^tm1Mae

Allele Symbol: Lias^tm1Mae

Genotype: Lias^tm1Mae/Lias^tm1Mae
either: 129S6/SvEvTac-Lias or (involves: 129S6/SvEvTac * C57BL/6J)

Genotype: Lias^tm1Mae/Lias⁺
either: 129S6/SvEvTac-Lias or (involves: 129S6/SvEvTac * C57BL/6J)

Additional - Lias^tm1Mae related