D2.B10-Dmd^mdx/J

Stock number: 013141
Strain synonyms: D2-mdx
Research areas: Cell Biology Research, Mouse/Human Gene Homologs, Neurobiology Research, Sensorineural Research

Description

The D2.B10 (DBA/2-congenic) Dmd^mdx mouse (also referred to as DBA/2J-mdx or D2-mdx mice) may be a superior Duchenne muscular dystrophy model as it better recapitulates several of the human characteristics of DMD myopathology (lower hind limb muscle weight, fewer myofibers, increased fibrosis and fat accumulation, and muscle weakness) relative to strains with this mutant allele on other genetic backgrounds.

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Detailed description

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 Dmd^mdx mutation in mice has a termination codon in exon 23 that is predicted to result in a truncated protein. Heterozygous females are viable and fertile with no gross phenotypic abnormalities. Homozygous females and hemizygous males are viable and fertile with myopathic features of DMD; although the myopathology is both less severe than the human disease course and variable by mouse strain genetic background.

The muscle pathology observed for C57BL/10ScSn-Dmd^mdx mice (also referred to as C57BL/10-mdx ; Stock No. 001801) includes active fiber necrosis, cellular infiltration, a wide range of fiber sizes, and numerous centrally nucleated regenerating fibers. However, adult C57BL/10-mdx mice fail to exhibit several of the skeletal muscle characteristics of DMD (such as smaller number of myofibers, accumulation of fat and fibrosis, insufficient myofiber regeneration, and loss of muscle weight). In addition, the C57BL/10 inbred strain is shown to possess greater muscle satellite cell self-renewal ability/efficiency than that of the DBA/2 inbred strain which may increase muscle regeneration/attenuate muscular dystrophy phenotype for MD mutations maintained on the C57BL/10 genetic background. As such, The Jackson Laboratory Repository created this DBA/2J-congenic Dmd^mdx mouse model, D2.B10-Dmd^mdx/J (also referred to as DBA/2J-mdx or D2-mdx; Stock No. 013141).

These DBA/2J-mdx mice may be expected to have a phenotype similar to other Dmd^mdx mouse models. That is, when compared to C57BL/10-mdx animals, DBA/2-congenic Dmd^mdx mice exhibit additional DMD characteristics such as lower hind limb muscle weight, fewer myofibers, increased fibrosis and fat accumulation, and remarkable muscle weakness. The DBA/2-congenic Dmd^mdx phenotype is attributed to diminished myofiber regeneration (rather than accelerated myofiber degeneration). Unlike C57BL/10-mdx mice, no increased incidence of spontaneous rhabdomyosarcoma-like tumors are reported for the DBA/2-congenic Dmd^mdx model.

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. This is the case for these DBA/2J-mdx mice (Stock No. 013141). It should be noted that the phenotype could vary from that originally described for C57BL/10-mdx (Stock No. 001801). We will modify the strain description if necessary as published results become available.

Development

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 (C57BL/10-mdx) mice are available from The Jackson Laboratory as Stock No. 001801. In 2010, some C57BL/10-mdx mice were backcrossed to DBA/2J inbred mice (Stock No. 000671) for several generations using a marker-assisted, speed congenic approach to generate the D2.B10-congenic strain (also referred to as DBA/2J-mdx) as Stock No. 013141.

Allele

Symbol: Dmd^mdx
Name: X linked muscular dystrophy
MGI accession ID: MGI:1856328
Generation method: Spontaneous
Marker symbol: Dmd
Marker name: dystrophin, 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.