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Genes & Alleles

Dmd;   Dmdmdx;

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Product Information

Strain Details

Type JAX® GEMM® Strain - Coisogenic Additional information on JAX® GEMM® Strains. Type JAX® GEMM® Strain - Mutant Strain Type JAX® GEMM® Strain - Spontaneous Mutation Mating System Homozygote x Hemizygote         (Female x Male) Species laboratory mouse H2 Haplotype b Generation F66 (03-JAN-08)

Appearance
black, affected
Related Genotype: a/a Dmd^mdx/Dmd^mdx or a/a Dmd^mdx/Y

Strain Description
The X-linked dystrophin gene (Dmd) is highly expressed in muscle cells and encodes a cytoskeletal protein which localizes to the inner face of the sarcolemma. Dystrophin molecules bind to cytoskeletal F-actin and transmembrane beta-dystroglycan as part of a complex, multimolecular unit that mediates signaling between the intracellular cytoskeleton and the extracellular matrix. The structure and localization also suggest that dystrophin is important for stabilizing the plasma membrane, particularly during contraction. The mdx mutation of Dmd is recessive and heterozygous females are visually indistinguishable from wild-type mice. Females homozygous and males hemizygous for the Dmd^mdx allele retain a normal lifespan and can survive up to two years. Like human patients who suffer from one of the most common neuromuscular diseases, Duchenne muscular dystrophy (DMD), the Dmd^mdx mutants do not express dystrophin and therefore have been routinely used as an animal model of the disease even though the resultant myopathology is much less severe compared to the human disease course.

Muscle from Dmd^mdx mutants is histologically normal early in postnatal development, but starting around 3 weeks muscle necrosis develops with some visible muscle weakness. Biochemical analysis of related pathologies includes elevated serum creatine kinase and pyruvate kinase levels, along with an accumulation of macrophages, both early markers of muscle degeneration. While skeletal limb muscles are characterized by a persistent and progressive degeneration and necrosis, this is offset by a regenerative response activated by satellite cells and muscle hypertrophy. The regenerating fibers are morphologically typified by small-caliber centrally nucleated fibers; nevertheless, the mice assume normal behavior. The muscles of Dmd^mdx mutants have an overall reduction in elasticity, making them more susceptible to injury due to lengthening-activation. Interestingly, the mutant leg muscles were found to initially develop normally, but the differentiation of regenerated myotubes into both fast and slow fiber types was significantly inhibited. The comparatively mild phenotype of the Dmd^mdx mice can, in part, be attributed to the compensatory function of the dystrophin-related protein utrophin, which is highly upregulated in regenerating muscle fibers in adult Dmd^mdx mutants. This functional redundancy was demonstrated in mice deficient for both of these sarcolemmal proteins where the observed muscular dystrophy was much more severe and led to a premature death in the dystophin/utrophin double mutants. Also, the muscle-specific transcription factor MYOD may also be involved in facilitating muscle regeneration in the mutant mice as Dmd^mdx mice also lacking MYOD exhibit a more severe dystrophy of the muscles. In contrast to limb muscles, the diaphragm muscles of Dmd^mdx mice do not undergo a significant regeneration phase such that the continuous dystrophy weakens these muscles with age. The specific twitch force, specific titanic force and maximum power are all reduced in the diaphragm of Dmd^mdx mutants.

Auditory function of Dmd^mdx mutants, as assessed by brainstem auditory evoked potentials, is altered leaving them more vulnerable to noise damage. In mouse cardiac myocytes, dystrophin colocalizes with L-type calcium channels; in Dmd^mdx mutants, the inactivation of these channels is reduced and voltage-dependant activation shifts to more positive potentials, providing evidence that the protein normally regulates calcium channel activity in cardiac tissue. In brain areas associated with learning, memory and cognitive tasks, dystrophin and its isoforms have been detected within postsynaptic specializations. In the Dmd^mdx mouse sympathetic superior cervical ganglion, postsynaptic nicotinic acetylcholine receptor complexes containing the alpha3 subtype are destabilized as assayed by immunocytochemical and immunoprecipitation techniques. That proper dystrophin function is linked in nervous tissue to synaptic ligand-gated ion channel organization raises intriguing possibilities regarding the pathologic mechanisms underlying the cognitive defects often seen in DMD patients. (reviewed by Watchko et al. 2002, Durbeej and Campbell 2002; Ahn and Kunkel 1993; Cook and Davisson 1991; Doolittle 1997; Monaco and Kunkel 1987; Tamura et al. 1993; Stevens and Faulkner 2000; Del Signore et al. 2002; Houzelstein et al. 1992; Sicinski et al. 1989; Deconinck et al. 1997; Grady et al. 1997; Earnshaw et al. 2002; Chen et al. 2002; D'Souza et al. 1995; Lynch et al. 2001; Carretta et al. 2001; Sadeghi et al. 2002; Lidov et al. 1995)

Strain Development
The spontaneous mutation Dmd^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.). Mice carrying the 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). C57BL/10ScSn-Dmd^mdx is maintained by sibling mating homozygous females with hemizygous males; mice can breed up to six months of age. In 2002, the strain had reached F49. (Bulfield et al., 1978 and 1984).

Related Disease (OMIM) Terms Muscular Dystrophy, Duchenne Type; DMD

Mammalian Phenotype Terms assigned by genotype Dmdmdx/Dmdmdx         C57BL/10ScSnJ muscle phenotype abnormal muscle morphology (MGI Ref ID J:7361) abnormal muscle fiber morphology (MGI Ref ID J:7361) variable muscle fiber size; progressive starting at 3 weeks of age development of electron-dense bodies in the mitochondria resulting in swelling and degenerating mitochondria, and disruption of the plasmalemma basal lamina the normal myofibrillar architecture of bands and lines disappears and myofilaments disintegrate and become misaligned dilated sarcoplasmic reticulum (MGI Ref ID J:7361) muscle degeneration (MGI Ref ID J:7361) progressive starting at 3 weeks of age myopathy (MGI Ref ID J:7361) progressive degenerative myopathy; increased severity with age skeletal muscle necrosis (MGI Ref ID J:7361) progressive starting at 9 weeks of age abnormal muscle physiology (MGI Ref ID J:3666) increased intracellular sodium concentration in muscle; increased severity with age muscular atrophy (MGI Ref ID J:7361) progressive starting at 3 weeks of age dystrophic muscle (MGI Ref ID J:7361) homeostasis/metabolism phenotype abnormal circulating enzyme level (MGI Ref ID J:7361) exhibit elevated blood levels of muscle creatine kinase and pyruvate kinase reproductive system phenotype reduced female fertility (MGI Ref ID J:7361) slight reduction in fertility other phenotype fibrosis (MGI Ref ID J:7361) exhibit mild muscle fibrosis, however there is no replacement of lost muscle by fat cells Dmdmdx/Dmdmdx         C57BL/10ScSn-Dmdmdx/J behavior/neurological phenotype abnormal grip strength (MGI Ref ID J:106640) performance is similar to that observed in double knockouts impaired coordination (MGI Ref ID J:106640) performance is similar to that observed in double knockouts hearing/vestibular/ear phenotype decreased brainstem auditory evoked potential (MGI Ref ID J:105938) significantly increased hearing threshold and prolonged brainstem auditory evoked potential peak and interpeak latencies after noise exposure increased susceptibility to noise-induced hearing loss (MGI Ref ID J:105938) daily exposure to noise for 1 month increased hearing threshold and prolonged brainstem auditory evoked potential peak and interpeak latencies Dmdmdx/Y         C57BL/10ScSnJ behavior/neurological phenotype abnormal motor capabilities/coordination/movement (MGI Ref ID J:7361) impaired coordination (MGI Ref ID J:7361) mild incoordination noticeable by 12 months of age tremors (MGI Ref ID J:7361) muscular tremors noticeable by 12 months of age muscle phenotype abnormal muscle morphology (MGI Ref ID J:7361) abnormal muscle fiber morphology (MGI Ref ID J:7361) variable muscle fiber size; progressive starting at 3 weeks of age development of electron-dense bodies in the mitochondria resulting in swelling and degenerating mitochondria, and disruption of the plasmalemma basal lamina the normal myofibrillar architecture of bands and lines disappears and myofilaments disintegrate and become misaligned dilated sarcoplasmic reticulum (MGI Ref ID J:7361) muscle degeneration (MGI Ref ID J:7361) progressive starting at 3 weeks of age myopathy (MGI Ref ID J:7361) progressive degenerative myopathy; increased severity with age skeletal muscle necrosis (MGI Ref ID J:7361) progressive starting at 9 weeks of age abnormal muscle physiology (MGI Ref ID J:3666) increased intracellular sodium concentration in muscle; increased severity with age muscular atrophy (MGI Ref ID J:7361) progressive starting at 3 weeks of age dystrophic muscle (MGI Ref ID J:7361) homeostasis/metabolism phenotype abnormal circulating enzyme level (MGI Ref ID J:7361) exhibit elevated blood levels of muscle creatine kinase and pyruvate kinase other phenotype fibrosis (MGI Ref ID J:7361) exhibit mild muscle fibrosis, however there is no replacement of lost muscle by fat cells Dmdmdx/Y         C57BL/10ScSn-Dmdmdx muscle phenotype abnormal skeletal muscle fiber morphology (MGI Ref ID J:9638) mice exhibit skeletal muscle fiber degeneration with phagocytosis unlike in wild type mice impaired muscle relaxation (MGI Ref ID J:9638) electromyograms reveal peudomyotonia unlike in wild type mice muscle degeneration (MGI Ref ID J:9638) mice exhibit skeletal muscle fiber degeneration with phagocytosis unlike in wild type mice myocardial fiber degeneration (MGI Ref ID J:9638) unlike in wild type mice, cardiac fiber degeneration with phagocytosis is observed cardiovascular system phenotype myocardial fiber degeneration (MGI Ref ID J:9638) unlike in wild type mice, cardiac fiber degeneration with phagocytosis is observed The following phenotype information may relate to a genetic background differing from this JAX® Mice strain. Dmdmdx/Y         B6.B10ScSn-Dmdmdx muscle phenotype abnormal skeletal muscle morphology (MGI Ref ID J:85088) muscles contain occasional patches of pale tissue which are primarily connective tissue abnormal skeletal muscle fiber morphology (MGI Ref ID J:85088) when mice are injected with the diazo dye EBD, dye is taken up by damaged muscle fibers to varying degrees, but preferentially into the hindlimb; uptake occurs because of focal breakdown of plasmalemma which is an early event in necrosis muscles are not stained homogeneously, but streaks of dye representing damaged muscle fibers are observed in the muscle fibers of the diaphragm and gluteus maximus; damage is less severe than in Fgf2/Fgf6/Dmd triple mutants dystrophic muscle (MGI Ref ID J:85088) mutants show dystrophic changes to the muscle fibers, although less severely than Fgf2/Fgf6/Dmd triple mutants

Gene & Allele Details

Allele Symbol		Dmdmdx
Allele Name		X linked muscular dystrophy
Common Name(s)		mdx; pke; pvruvate kinase expression;
Strain of Origin		C57BL/10ScSn
Gene Symbol and Name		Dmd, dystrophin, muscular dystrophy
Chromosome		X
Gene Common Name(s)		BMD; CMD3B; DNADMD1; DXS142; DXS164; DXS206; DXS230; DXS239; DXS268; DXS269; DXS270; DXS272; Dp427; Duchenne muscular dystrophy; RATDMD; X-linked muscular dystrophy; mdx; pke; pyruvate kinase expression;
Molecular Note		This mutation arose in 1981 in a C57BL/10ScSn colony at University of Leicester. A C-to-T transition occured at position 3185, resulting in a termination codon in place of a glutamine codon. This mutation is predicted to produce a truncated protein. [MGI Ref ID J:102707] [MGI Ref ID J:40541] [MGI Ref ID J:9866]

Control Information

Allele	Control
Dmdmdx	000476 C57BL/10ScSnJ
Dmdmdx	000666 C57BL/10SnJ
Considerations for Choosing Controls

Colony Maintenance

Diet Information	LabDiet® 5K52/5K67

Related Strains

Strains carrying other alleles of Dmd

002388	B6Ros.Cg-Dmdmdx-2Cv/J
002377	B6Ros.Cg-Dmdmdx-3Cv/J
002378	B6Ros.Cg-Dmdmdx-4Cv/J
002379	B6Ros.Cg-Dmdmdx-5Cv/J

View Strains carrying other alleles of Dmd     (4 strains)

Additional Web Information

Genetic Quality Control Annual Report
JAX^® NOTES, Summer 1991; 446. C57BL/10ScSn-mdx/J.

Animal Health Reports

Room Number           AX6

Research Applications

This mouse can be used to support research in many areas including:

Dmd^mdx related

Cell Biology Research
Signal Transduction

Mouse/Human Gene Homologs
muscular dystrophy (Duchenne and Becker)

Neurobiology Research
Neuromuscular Defects

Sensorineural Research
Cataracts

References

Selected Reference(s)

Bulfield G; Siller WG; Wight PA; Moore KJ. 1984. X chromosome-linked muscular dystrophy (mdx) in the mouse. Proc Natl Acad Sci U S A 81(4):1189-92. [PubMed: 6583703]  [MGI Ref ID J:7361]

Ryder-Cook AS; Sicinski P; Thomas K; Davies KE; Worton RG; Barnard EA; Darlison MG; Barnard PJ. 1988. Localization of the mdx mutation within the mouse dystrophin gene. EMBO J 7(10):3017-21. [PubMed: 2903046]  [MGI Ref ID J:9438]

Sicinski P; Geng Y; Ryder-Cook AS; Barnard EA; Darlison MG; Barnard PJ. 1989. The molecular basis of muscular dystrophy in the mdx mouse: a point mutation. Science 244(4912):1578-80. [PubMed: 2662404]  [MGI Ref ID J:9866]

Additional References

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Price and Supply Information

Strain Name:	C57BL/10ScSn-Dmdmdx/J
Stock Number:	001801

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Supply Details

Standard Supply	Level 2. Up to 100 mice. Larger quantities or custom orders arranged upon request.
Supply Notes	Shipped at a specific age in weeks. Mice at a precise age in days, littermates and retired breeders are also available. Strains that must be genotyped are not available until five to seven weeks of age. Genomic DNA is available for this strain from the Mouse DNA Resource.
Licensing	See General Terms and Conditions below
Control Information	View Control Information in Strain Details.

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The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX^® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX^® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX^® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project.

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