STOCK Utrn^tm1Jrs Dmd^mdx/J

Stock number: 016622
Product name: mdx/utrn -
Research areas: Cardiovascular Research, Cell Biology Research, Mouse/Human Gene Homologs, Neurobiology Research, Research Tools, Sensorineural Research

Description

Mice homozygous for the Utrn^tm1Jrs and Dmd^mdx exhibit an onset of skeletal muscle dystrophy as early as 4 weeks of age and are a model for Duchenne Type Muscular Dystrophy.

Detailed description

Mice homozygous for the Utrn^tm1Jrs and Dmd^mdx alleles have a lifespan of 4 to 20 weeks, with only 50% surviving beyond 8 weeks of age. As early as 3 weeks of age homozygotes display growth delays, are smaller than wildtype controls and exhibit skeletal muscle dystrophy with abnormal waddling gait at 4 weeks of age. At 10 weeks of age, double mutants exhibit skeletal muscle degeneration, necrosis and interstitial fibrosis, as well as abnormal echocardiography results. By 15 weeks of age, the double homozygotes develop dilated cardiomyopathy. The double mutants exhibit kyphosis, compromised systolic and diastolic function, progressive fibrosis throughout the heart, cardiomyocyte membrane damage, ventricular cellular necrosis, and disorganized mitochondria and myofibrils in cardiomyocytes.

Development

These double mutant mice were produced by breeding mice carrying the Utrn^tm1Jrs targeted mutation and the Dmd^mdx spontaneous mutation.

To generate the Utrn^tm1Jrs targeted mutation, a targeting vector containing PGK-Neo cassette was used to disrupt an exon encoding the beginning of the cysteine-rich region of the protein. The construct was electroporated into 129 derived R1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts. The mice were maintained on a mixed B6;129 background.

The Dmd^mdx spontaneous mutation arose just prior to 1977 at the Agricultural Research Council's Poultry Research Centre, U.K., in C57BL/10ScSn mice obtained from M. Festing (MRC Laboratory Animals Centre, Carshalton, Surrey, U.K.). Mice carrying the Dmd^mdx allele were imported to The Jackson Laboratory in 1984 by Dr. Thomas Roderick, who received them from Dr. Karen Moore (Department of Genetics, University of California, Berkley). A C-to-T transition occurred at position 2983(ENSMUST00000114000 chrX:g.83803333 C>T; p.Q995*), resulting in a termination codon in place of a glutamine codon codon within exon 23 of the dystrophin muscular dystrophy gene (Dmd) on the X chromosome [note that Sicinski et al., 1989 originally reported termination codon at position 3185].

Allele

Symbol: Utrn^tm1Jrs
Name: targeted mutation 1, Joshua R Sanes
MGI accession ID: MGI:2148539
Generation method: Targeted
Attributes: Null/Knockout
Synonyms: uko; utrn-
Marker symbol: Utrn
Marker name: utrophin
Marker synonyms: DMDL; DRP; DRP1; DRP-1; G-utrophin
Chromosome: 10
Strain of origin: (129X1/SvJ x 129S1/Sv)F1-Kitl⁺
Molecular note: A neomycin resistance cassette replaced 2.7 kb of sequence including 52 bp of the exon that encodes the beginning of the C-terminal cysteine rich region. RT-PCR analysis demonstrated that a mutant transcript carrying the deletion was made in homozygous and heterozygous mice. Western blot analysis on extracts of muscle or lung tissue derived from homozygous mice confirmed that no detectable protein was expressed from this allele.

Allele

Symbol: Dmd^mdx
Name: X linked muscular dystrophy
MGI accession ID: MGI:1856328
Generation method: Spontaneous
Synonyms: mdx; pke; pyruvate kinase expression
Marker symbol: Dmd
Marker name: dystrophin, muscular dystrophy
Marker synonyms: BMD; CMD3B; DNADMD1; Dp427; Dp71; Duchenne muscular dystrophy; DXS142; DXS164; DXS206; DXS230; DXS239; DXS268; DXS269; DXS270; DXS272; dys; mdx; MRX85; pke; X-linked muscular dystrophy
Chromosome: X
Strain of origin: C57BL/10ScSn
Molecular note: This mutation arose in 1981 in a C57BL/10ScSn colony at University of Leicester. A C-to-T substitution in the CAA codon in exon 23 (ENSMUST00000114000 chrX:g.83803333C>T; c.2983C>T; p.Q995*) results in a termination codon (TAA) in place of a glutamine codon. This allele is predicted to produce a truncated protein.