B10ScSn.Cg-Utrn^tm1Ked Dmd^mdx/J

Stock number: 019014
Product name: B10ScSn.utr/mdx
Research areas: Cardiovascular Research, Cell Biology Research, Developmental Biology Research, Internal/Organ Research, Mouse/Human Gene Homologs, Neurobiology Research, Reproductive Biology Research, Sensorineural Research

Description

This C57BL/10ScSn-congenic utrophin/dystrophin double mutant strain (B10ScSn.utr/mdx) combines dystrophin-deficiency with postsynaptic neuromuscular dysfunction, and may be useful in studying neuromuscular junctions and hereditary neuropathies, specifically Duchenne muscular dystrophy.

Detailed description

Female mice that are homozygous for the Utrn^tm1Ked allele and the Dmd^mdx allele, and male mice that are homozygous for the Utrn^tm1Ked allele and hemizygous for the Dmd^mdx allele, exhibit a more severe phenotype than single Dmd^mdx mutants: earlier onset of muscle dystrophy (degeneration, macrophage infiltration and necrosis), weight loss after weaning, joint contractures, kyphosis, dystrophy of extraocular muscles, abnormal electrocardiograms, infertility and premature death. Growth retardation onset is at weaning. By 4 of 6 weeks of age, the double mutants exhibit reduced body weight, reduced mobility, abnormal breathing pattern and slack posture. Muscle weakness and kyphosis (curvature of the spine) is progressive and the double mutant mice develop a waddling gait. Necrosis of the diaphragm muscle is observed in 6 day old double mutant mice. Muscle fibers with centralized nuclei are seen in 2 week old double mutants. 8 to 10 week old mutants exhibit a muscular dystrophy phenotype similar to mice homozygous for the Dmd^mdx allele with variation in muscle fiber size, necrosis, fibrosis, macrophage infiltration and centrally nucleated muscle fibers. Ultrastructural examination of postsynaptic motor endplate regions of neuromuscular and myotendinous junctions of the soleus and diaphragm muscle from 10 week old double mutant mice reveals a lack of junctional folds at the postsynaptic membrane. Female mice that are homozygous for the Utrn^tm1Ked allele and the Dmd^mdx allele, and male mice that are homozygous for the Utrn^tm1Ked allele and hemizygous for the Dmd^mdx allele, exhibit clinical symptoms as early as 4 weeks of age and die by 20 weeks of age.

In an attempt to offer alleles on well-characterized or multiple genetic backgrounds, alleles are frequently moved to a genetic background different from that on which an allele was first characterized. It should be noted that the phenotype of these B10ScSn.utr/mdx mice could vary from that originally described on a C57BL/10ScSn;DBA/2;C57BL/6 mixed genetic background. We may modify the strain description if necessary as published results become available. C57BL/10ScSn;DBA/2;C57BL/6 mixed genetic background utr/mdx mice are described and available as Stock No. 014563.

Development

This C57BL/10ScSn-congenic utrophin/dystrophin double mutant strain (B10ScSn.utr/mdx) harbors two mutations; the utr null allele (Utrn^tm1Ked) and the spontaneous X-linked muscular dystrophy mutation (Dmd^mdx).

The utr null allele was designed by Dr. Kay E. Davies (University of Oxford) with a PGK-neomycin cassette disrupting exon 7 of the utrophin gene on chromosome 10. C57BL/10ScSn-congenic mice harboring the utr null allele are described and available from The Jackson Laboratory Repository as Stock No. 018802.

The spontaneous mutation "X chromosome-linked muscular dystrophy" (mdx) has as a C-to-T transition resulting in a termination codon at position 2983 (ENSMUST00000114000 chrX:g.83803333 C>T; p.Q995*) 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]. C57BL/10ScSn-Dmd^mdx mice are described and available from The Jackson Laboratory Repository as Stock No. 001801.

To generate this B10ScSn.utr/mdx double mutant line (Stock No. 019014), B10ScSn-congenic utr^+/- males (Stock No. 018802) were bred with B10ScSn.Dmd^mdx/mdx females (Stock No. 001801). Thereafter, our live colony is maintained by breeding females heterozygous for Utrn^tm1Ked and homozygous for Dmd^mdx with males wildtype at the Utrn locus and hemizygous for Dmd^mdx. That is, utr^+/-;mdx^-/- females may be bred with mdx^-/Y males from the colony or with C57BL/10ScSn-Dmd^mdx males (Stock No. 001801).

Allele

Symbol: Utrn^tm1Ked
Name: targeted mutation 1, Kay E Davies
MGI accession ID: MGI:2148589
Generation method: Targeted
Attributes: Null/Knockout
Synonyms: Utr^-
Marker symbol: Utrn
Marker name: utrophin
Marker synonyms: DMDL; DRP; DRP1; G-utrophin
Chromosome: 10
Strain of origin: (129X1/SvJ x 129S1/Sv)F1-Kitl⁺
Molecular note: Insertion of a neomycin cassette into exon 7. No protein was detected in extracts derived from kidney, lung or brain of homozygous mice as assayed by Western blot analysis.

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.