B6.129S7-Asl^tm1Brle/J

Stock number: 018830
Research areas: Cardiovascular Research, Dermatology Research, Developmental Biology Research, Immunology, Inflammation and Autoimmunity Research, Internal/Organ Research, Research Tools

Description

These Asl (argininosuccinate lyase) conditional hypopmorphic mice are useful in studies of human Argininosuccinic aciduria (ASA), characterized by a persistent intellectual impairment, delayed motor skills and progressive hepatic disease.

Detailed 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 (see SNP note below). All animals in the donator's colony are black, suggesting that Tyr^c-Brd has been bred out.

A 32 SNP (single nucleotide polymorphism) panel analysis, with 27 markers covering all 19 chromosomes and the X chromosome, as well as 5 markers that distinguish between the C57BL/6J and C57BL/6N substrains, was performed on the rederived living colony at The Jackson Laboratory Repository. Ten markers throughout the genome were segregating for 129, suggesting an incomplete backcross.

Allele

Symbol: Asl^tm1Brle
Name: targeted mutation 1, Brendan Lee
MGI accession ID: MGI:5308970
Generation method: Targeted
Attributes: Conditional ready (e.g. floxed); Hypomorph
Marker symbol: Asl
Marker name: argininosuccinate lyase
Chromosome: 5
Strain of origin: 129S7/SvEvBrd-Hprt^b-m2
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.