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.
IMR Colony, The Jackson Laboratory
Female mice that are homozygous for the Utrntm1Ked allele and the Dmdmdx allele, and male mice that are homozygous for the Utrntm1Ked allele and hemizygous for the Dmdmdx allele, exhibit a more severe phenotype than single Dmdmdx 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 Dmdmdx 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 Utrntm1Ked allele and the Dmdmdx allele, and male mice that are homozygous for the Utrntm1Ked allele and hemizygous for the Dmdmdx 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.
This C57BL/10ScSn-congenic utrophin/dystrophin double mutant strain (B10ScSn.utr/mdx) harbors two mutations; the utr null allele (Utrntm1Ked) and the spontaneous X-linked muscular dystrophy mutation (Dmdmdx).
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-Dmdmdx 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.Dmdmdx/mdx females (Stock No. 001801). Thereafter, our live colony is maintained by breeding females heterozygous for Utrntm1Ked and homozygous for Dmdmdx with males wildtype at the Utrn locus and hemizygous for Dmdmdx. That is, utr+/-;mdx-/- females may be bred with mdx-/Y males from the colony or with C57BL/10ScSn-Dmdmdx males (Stock No. 001801).
|Allele Name||X linked muscular dystrophy|
|Allele Synonym(s)||mdx; pke; pyruvate kinase expression|
|Gene Symbol and Name||Dmd, dystrophin, muscular dystrophy|
|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.|
|Allele Name||targeted mutation 1, Kay E Davies|
|Allele Type||Targeted (Null/Knockout)|
|Gene Symbol and Name||Utrn, utrophin|
|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.|
|Mutations Made By|| |
Kay Davies, University of Oxford
Dmdmdx is on the X chromosome. On a C57BL/10ScSn;DBA/2;C57BL/6 mixed genetic background, females homozygous for both Utrntm1Ked and Dmdmdx, and males homozygous for Utrntm1Ked and hemizygous for Dmdmdx, exhibit clinical symptoms as early as 4 weeks of age and die by 20 weeks of age. When maintaining a live colony, females heterozygous for Utrntm1Ked and homozygous for Dmdmdx may be bred with males wildtype at the Utrn locus and hemizygous for Dmdmdx. That is, utr+/-;mdx-/- females may be bred with mdx-/Y males from the colony or with C57BL/10ScSn-Dmdmdx males (Stock No. 001801).
When using the B10ScSn.utr/mdx mouse strain in a publication, please cite the originating article(s) and include JAX stock #019014 in your Materials and Methods section.