Description

Strain Information

Type Congenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Additional information on Congenic nomenclature. Mating System Wild-type x Heterozygote         (Female x Male)   25-OCT-12 Mating System Heterozygote x Wild-type         (Female x Male)   25-OCT-12 Species laboratory mouse Generation F?pN1+N0 (24-JAN-13) Generation Definitions   Donating Investigator Brendan Lee,   Baylor College of Medicine

Description
Asl (argininosuccinate lyase) encodes a key enzyme in the urea cycle that catalyzes the breakdown of argininosuccinate to dicarboxylic acid fumarate and the amino acid arginine, a component of the citrulline-nitric oxide (Cit-NO)cycle. Humans with ASL deficiency develop Argininosuccinic aciduria (ASA), characterized by a persistent intellectual impairment, delayed motor skills and progressive hepatic disease.

This targeted mutation strain carries a FRT-flanked neomycin cassette in intron 9 that decreases expression and activity of the gene. These hypomorphic mice are reported to express 15-20% normal levels of protein. Homozygous mice die at 3-4 weeks of age. They show severe postnatal growth retardation, abnormal hair patterning, multiple organ system dysfunction, hyperammonemia, and nitric oxide deficiency. Liver transaminase levels are elevated in plasma, renal creatinine clearance is decreased, and systolic/diastolic blood pressures are elevated compared to wild-type mice. Histological defects are found in multiple organs, involving the immune, hematopoietic, and cardiovascular systems. Heterozygous animals have no phenotype. FLP excision of the neomycin cassette results in phenotypically normal mice.

LoxP sites in introns 6 and 9 make this a conditional allele for generating tissue-specific Cre-generated knockouts. Excision of exons 7-9 stops protein expression.

Development
A loxP site was inserted in intron 6 and an FRT-neomycin-FRT-loxP cassette was introduced to intron 9 using AB2.2 129S7/SvEvBrd-Hprt1⁺-derived embryonic stem (ES) cells. This strain was backcrossed 5 times to an albino C57BL/6 strain by the donating laboratory. All animals in the donator's colony are black, suggesting that Tyr^c-Brd has been bred out.

Control Information

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

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI

- Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested. Argininosuccinic Aciduria   (ASL)

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

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

Asl^tm1Brle/Asl^tm1Brle

        involves: 129S7/SvEvBrd

• mortality/aging
• premature death
  • mice die within the first 3 to 4 weeks due to multiorgan failure   (MGI Ref ID J:180208)
  • however, mice treated with sodium nitrite, arginine, arginine and sodium benzoate, or all three therapies exhibit improved survival   (MGI Ref ID J:180208)
• immune system phenotype
• decreased lymphocyte cell number
  • in the spleen and thymus   (MGI Ref ID J:180208)
• decreased spleen germinal center number   (MGI Ref ID J:180208)
• increased macrophage cell number
  • in the thymus cortex   (MGI Ref ID J:180208)
• increased spleen red pulp amount   (MGI Ref ID J:180208)
• thymus cortex hypoplasia
  • thin   (MGI Ref ID J:180208)
• homeostasis/metabolism phenotype
• abnormal circulating amino acid level
  • mice exhibit increased plasma citrulline and decreased arginine levels compared with wild-type mice   (MGI Ref ID J:180208)
• abnormal nitric oxide homeostasis
  • decreased nitrosylation in the liver and heart   (MGI Ref ID J:180208)
• decreased circulating alanine transaminase level   (MGI Ref ID J:180208)
• decreased circulating aspartate transaminase level   (MGI Ref ID J:180208)
• increased circulating ammonia level   (MGI Ref ID J:180208)
• cardiovascular system phenotype
• abnormal myocardial fiber morphology
  • atrophic in the myocardium   (MGI Ref ID J:180208)
• decreased vasodilation
  • impaired in response to acetylcholine treatment   (MGI Ref ID J:180208)
  • however, relaxation in response to sodium nitroprusside is normal   (MGI Ref ID J:180208)
• increased systemic arterial diastolic blood pressure
  • however, mice treated with sodium nitrite, arginine and sodium benzoate exhibit normalizes blood pressure   (MGI Ref ID J:180208)
• increased systemic arterial systolic blood pressure
  • however, mice treated with sodium nitrite, arginine and sodium benzoate exhibit normalizes blood pressure   (MGI Ref ID J:180208)
• integument phenotype
• abnormal coat/ hair morphology
  • abnormal hair patterning by 2 weeks of age   (MGI Ref ID J:180208)
• abnormal dermal layer morphology
  • atrophic   (MGI Ref ID J:180208)
• abnormal hair follicle morphology
  • small and disorganized   (MGI Ref ID J:180208)
• • small hair follicles   (MGI Ref ID J:180208)
• epidermal atrophy   (MGI Ref ID J:180208)
• growth/size phenotype
• decreased body weight
  • at 3 and 4 weeks of age   (MGI Ref ID J:180208)
  • however, mice treated with sodium nitrite or sodium nitrite, arginine and sodium benzoate exhibit increased weight   (MGI Ref ID J:180208)
• postnatal growth retardation
  • by 2 weeks of age   (MGI Ref ID J:180208)
• renal/urinary system phenotype
• abnormal renal glomerulus morphology
  • smaller than in wild-type mice   (MGI Ref ID J:180208)
• decreased creatinine clearance   (MGI Ref ID J:180208)
• muscle phenotype
• abnormal myocardial fiber morphology
  • atrophic in the myocardium   (MGI Ref ID J:180208)
• decreased vasodilation
  • impaired in response to acetylcholine treatment   (MGI Ref ID J:180208)
  • however, relaxation in response to sodium nitroprusside is normal   (MGI Ref ID J:180208)
• hematopoietic system phenotype
• abnormal erythrocyte morphology
  • mice exhibit more numerous acanthocytes and fewer spherocytes than in wild-type mice   (MGI Ref ID J:180208)
• • acanthocytosis
    • more numerous acanthocytes than in wild-type mice   (MGI Ref ID J:180208)
• decreased lymphocyte cell number
  • in the spleen and thymus   (MGI Ref ID J:180208)
• decreased spleen germinal center number   (MGI Ref ID J:180208)
• increased macrophage cell number
  • in the thymus cortex   (MGI Ref ID J:180208)
• increased spleen red pulp amount   (MGI Ref ID J:180208)
• thymus cortex hypoplasia
  • thin   (MGI Ref ID J:180208)

View Research Applications

Research Applications

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

Cardiovascular Research
Heart Abnormalities

Dermatology Research
Skin and Hair Texture Defects

Developmental Biology Research
Growth Defects
      Growth Defects (homozygous)
Postnatal Lethality
      Homozygous

Immunology, Inflammation and Autoimmunity Research

Internal/Organ Research
Heart Abnormalities
Kidney Defects
Liver Defects
Lymphoid Tissue Defects
Spleen Defects

Research Tools
Cre-lox System
      loxP-flanked Sequences
FLP-FRT System
      FRT-flanked Sequences

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Asltm1Brle
Allele Name		targeted mutation 1, Brendan Lee
Allele Type		Targeted (other)
Common Name(s)		AslNeo;
Mutation Made By		Brendan Lee,   Baylor College of Medicine
Strain of Origin		129S7/SvEvBrd-Hprt
Gene Symbol and Name		Asl, argininosuccinate lyase
Chromosome		5
Gene Common Name(s)		2510006M18Rik; ASAL; RIKEN cDNA 2510006M18 gene;
Molecular Note		A loxP site was inserted downstream of exon 7. An FRT-flanked neo cassette with a 3' loxP site was inserted downstream of exon 9. Western blot analysis confirmed a reduction in protein expression. This allele is hypomorphic. [MGI Ref ID J:180208]

Genotyping

Genotyping Information

Genotyping Protocols

Asl^tm1Brle,

Separated MCA

Asl^tm1Brle, Separated PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Erez A; Nagamani SC; Shchelochkov OA; Premkumar MH; Campeau PM; Chen Y; Garg HK; Li L; Mian A; Bertin TK; Black JO; Zeng H; Tang Y; Reddy AK; Summar M; O'Brien WE; Harrison DG; Mitch WE; Marini JC; Aschner JL; Bryan NS; Lee B. 2011. Requirement of argininosuccinate lyase for systemic nitric oxide production. Nat Med 17(12):1619-26. [PubMed: 22081021]  [MGI Ref ID J:180208]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX18

Colony Maintenance

Breeding & Husbandry	Heterozygotes are viable and fertile. Homozygotes die at 3-4 weeks of age.
Mating System	Wild-type x Heterozygote         (Female x Male)   25-OCT-12
	Heterozygote x Wild-type         (Female x Male)   25-OCT-12

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

Control Information

	Control
	Wild-type male from the colony
	000664 C57BL/6J
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

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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.

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Terms of Use

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General Terms and Conditions

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