Mice homozygous/hemizygous for the spontaneous Dmdmdx allele and homozygous for the human micro-dystrophin transgene exhibit partially improved cardiac muscle function and muscle histopathology as compared to mdx mice and may be useful for studying Duchenne muscular dystrophy.
Dongsheng Duan, University of Missouri
Duchenne muscular dystrophy (DMD) is a progressive muscular disorder caused by an imbalance between muscle degeneration and regeneration resulting in muscle degeneration, necrosis, accumulation of fat and fibrosis, and insufficient regeneration/loss of myofibers. The genetic cause of DMD are mutations of the dystrophin muscular dystrophy gene (DMD) on the X chromosome. The Dmdmdx mutation in mice has a termination codon in exon 23 that is predicted to result in a truncated protein. Homozygous females and hemizygous males develop the myopathic features of DMD; although the myopathology is both less severe than the human disease course.
The conditional Tg(Myh6-DMD*)271Dua transgene carries a deletion of the hinge 2 region through repeat 15 under the control of the rat cardiac muscle specific alpha myosin (Myh6 or α-MHC) promoter. This micro-dystrophin transgene is flanked by loxP sites. When the transgene is combined with the mdx allele, the donating investigator reports that homozygous mice exhibit partially improved cardiac muscle function and histopathology as compared to FVB.B10-Dmdmdx mice.
The spontaneous mutation "X chromosome-linked muscular dystrophy" (mdx) 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.). The mdx mutation was identified 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]. Dr. Duan from the University of Missouri introgressed the Dmdmdx allele from C57BL/10ScSn-Dmdmdx/J to the FVB/NJ inbred strain for more than 5 generations.
The transgenic construct contains a loxP-flanked full length human dystrophin gene modified by the deletion of the Hinge 2 region through repeat 15 to generate a micro-dystrophin cDNA under the control of the rat cardiac muscle specific alpha myosin (Myh6 or α-MHC) promoter. The transgene was microinjected into the pronucleus of fertilized FVB/N mouse eggs. Founder line 271 was established and crossed to FVB.B10-Dmdmdx/J mice for 2 generations.
|Expressed Gene||DMD, dystrophin, human|
|Site of Expression|
|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||transgene insertion 271, Dongsheng Duan|
|Allele Type||Transgenic (Inserted expressed sequence, Humanized sequence)|
|Gene Symbol and Name||Tg(Myh6-DMD*)271Dua, transgene insertion 271, Dongsheng Duan|
|Promoter||Myh6, myosin heavy chain 6, rat|
|Expressed Gene||DMD, dystrophin, human|
|Strain of Origin||FVB/N|
|Molecular Note||The transgenic construct contains a loxP-flanked full length human dystrophin gene modified by the deletion of the Hinge 2 region through repeat 15 to generate a micro-dystrophin cDNA under the control of the rat cardiac muscle specific alpha myosin (Myh6 or alpha-MHC) promoter.|
While maintaining a live colony, mice carrying the X-linked mdx allele are bred as homozygote female x hemizygote male. Mice homozygous for the transgene are viable and fertile.
When using the FVB.Cg-Dmdmdx Tg(Myh6-DMD*)271Dua/Mmjax mouse strain in a publication, please cite the originating article(s) and include MMRRC stock #41198 in your Materials and Methods section.