Description

Strain Information

Type Congenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Additional information on Congenic nomenclature. Mating System Homozygote x Homozygote         (Female x Male)   18-DEC-12 Species laboratory mouse Generation N8+F1 (29-JUN-11) Generation Definitions   Donating Investigator Kevin Campbell,   University of Iowa

Description
Mice homozygous for this targeted mutation are viable, fertile and show a normal growth rate. Mice develop a slowly progressive muscular dystrophy. By the age of 2 months, a few individual necrotic and centrally nucleated fibers can be detected throughout the muscle; the number increases with age. By 8 months, the muscle develops all of the pathological characteristics of muscular dystrophy (e.g. regenerating fibers, split fibers, muscle necrosis with macrophage infiltration and fat replacement). The severity of the pathology varies in different muscles. Muscle fibers are defective in Ca²⁺-dependent sarcolemma resealing/repair. No protein product from the targeted gene is detected in skeletal muscle microsomes. This mutant mouse strain represents a model that may be useful in studies of muscle disease and repair.

Development
A targeting vector containing a neomycin resistance gene was use to replace a 12 kb region containing the last three coding exons of the gene, including the exons coding for the transmembrane domain. The construct was electroporated into (129X1/SvJ x 129S1/Sv)F1-Kitl⁺-derived R1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into blastocysts. This strain was backcrossed to C57BL/6 for seven generations by the donating laboratory.

Control Information

	Control
	000664 C57BL/6J
Considerations for Choosing Controls

Related Strains

Strains carrying   Dysf^tm1Kcam allele

006830

129-Dysftm1Kcam/J

View Strains carrying   Dysf^tm1Kcam     (1 strain)

Strains carrying other alleles of Dysf

000646	A/J
011128	B10.SJL-Dysfim/AwaJ
012767	B6.A-Dysfprmd/GeneJ
017917	B6.Cg-Dysfprmd Prkdcscid/J
017644	B6;129S6-Dysftm2.1Kcam/J
000686	SJL/J

View Strains carrying other alleles of Dysf     (6 strains)

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI

- Model with phenotypic similarity to human disease where etiologies involve orthologs. Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

Miyoshi Muscular Dystrophy 1; MMD1
Muscular Dystrophy, Limb-Girdle, Type 2B; LGMD2B

- Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested. Myopathy, Distal, with Anterior Tibial Onset; DMAT   (DYSF)

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

The following phenotype information may relate to a genetic background differing from this JAX^® Mice strain.

Dysf^tm1Kcam/Dysf^tm1Kcam

        involves: 129S1/Sv * 129X1/SvJ * C57BL/6

• muscle phenotype
• abnormal muscle regeneration
  • in response to sarcolemma injuries, mutant skeletal muscle fibers display sub-sarcolemmal vesicle accumulations, whereas wild-type damaged fibers exhibit only dysferlin-enriched membrane patches   (MGI Ref ID J:83126)
  • unlike wild-type muscle fibres, mutant skeletal muscle fibres are defective in Ca²⁺-dependent sarcolemma resealing, indicating a disruption of the muscle membrane repair machinery   (MGI Ref ID J:83126)
• abnormal sarcolemma morphology
  • plasma membrane disruptions are identified with Evans blue by 8 months of age   (MGI Ref ID J:83126)
  • however, minimal sarcolemma damage is detected in mutant muscle after exercise, indicating the presence of a functional dystrophin-glycoprotein complex (DGC) and stable sarcolemma   (MGI Ref ID J:83126)
• centrally nucleated skeletal muscle fibers
  • ~10% of all fibers in mutant skeletal muscle are centrally nucleated by 2 months of age, 20% by 4 months of age, and 48% and 65% by 8 and 10 months, respectively   (MGI Ref ID J:83126)
• dystrophic muscle
  • homozygotes develop a slowly progressive muscular dystrophy at the level of single muscle fibers, as evidenced by the presence of individual Evans-blue positive fibers   (MGI Ref ID J:83126)
  • the % of centrally nucleated fibers increases with age, with a few individual necrotic and centrally nucleated fibers first evident at 2 months of age   (MGI Ref ID J:83126)
  • by 8 months of age, dystrophic skeletal muscle exhibits regenerating fibers, split fibers, and muscle necrosis with macrophage infiltration, and fat replacement   (MGI Ref ID J:83126)
  • the severity of muscle pathology varies in different skeletal muscles   (MGI Ref ID J:83126)
• increased variability of skeletal muscle fiber size
  • at 9 months of age, a significantly greater muscle fiber size variation is noted in mutant skeletal muscle than in wild-type muscle   (MGI Ref ID J:83126)
• skeletal muscle fiber degeneration
  • active skeletal muscle regeneration occurs in response to muscle degeneration, as evidenced by the presence of centrally nucleated skeletal muscle fibers and increased variability in fiber size   (MGI Ref ID J:83126)
• skeletal muscle fiber necrosis
  • significant skeletal muscle necrosis with macrophage infiltration and fat replacement is evident by 8 months of age   (MGI Ref ID J:83126)
• homeostasis/metabolism phenotype
• increased circulating creatine kinase level
  • homozygotes exhibit a several-fold increase in serum creatine kinase levels relative to wild-type mice   (MGI Ref ID J:83126)

View Research Applications

Research Applications

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

Mouse/Human Gene Homologs
muscular dystrophy, limb-girdle
      type 2B

Neurobiology Research
Muscular Dystrophy
      Limb-Girdle type

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Dysftm1Kcam
Allele Name		targeted mutation 1, Kevin P Campbell
Allele Type		Targeted (knock-out)
Mutation Made By		Kevin Campbell,   University of Iowa
Strain of Origin		(129X1/SvJ x 129S1/Sv)F1-Kitl<+>
ES Cell Line Name		R1
ES Cell Line Strain		(129X1/SvJ x 129S1/Sv)F1-Kitl<+>
Gene Symbol and Name		Dysf, dysferlin
Chromosome		6
Gene Common Name(s)		2310004N10Rik; AI604795; D6Pas3; DNA segment, Chr 6, Pasteur Institute 3; FER1L1; LGMD2B; MMD1; RIKEN cDNA 2310004N10 gene; expressed sequence AI604795;
Molecular Note		12 kb of sequences at the 3' end of the gene were replaced with a neomycin resistance cassette via homologous recombination. The gene targeting event results in deletion of the last 3 coding exons including the transmembrane domain. Absence of gene expression in homozygous mutant animals was confirmed by Western blot analysis of skeletal muscle microsomes. [MGI Ref ID J:83126]

Genotyping

Genotyping Information

Genotyping Protocols

Dysf^tm1Kcamalternate1, Separated PCR
Generic Neo Quantitative PCR-QPCR- 1.2, QPCR

Download the Genotyping Protocol for Dysf^tm1Kcam from Kevin Campbell, University of Iowa.

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Bansal D; Miyake K; Vogel SS; Groh S; Chen CC; Williamson R; McNeil PL; Campbell KP. 2003. Defective membrane repair in dysferlin-deficient muscular dystrophy. Nature 423(6936):168-72. [PubMed: 12736685]  [MGI Ref ID J:83126]

Additional References

Dysf^tm1Kcam related

Barnabei MS; Metzger JM. 2012. Ex vivo stretch reveals altered mechanical properties of isolated dystrophin-deficient hearts. PLoS One 7(3):e32880. [PubMed: 22427904]  [MGI Ref ID J:186918]

Beedle AM; Nienaber PM; Campbell KP. 2007. Fukutin-related protein associates with the sarcolemmal dystrophin-glycoprotein complex. J Biol Chem 282(23):16713-7. [PubMed: 17452335]  [MGI Ref ID J:122734]

Han R; Bansal D; Miyake K; Muniz VP; Weiss RM; McNeil PL; Campbell KP. 2007. Dysferlin-mediated membrane repair protects the heart from stress-induced left ventricular injury. J Clin Invest 117(7):1805-13. [PubMed: 17607357]  [MGI Ref ID J:124212]

Han R; Frett EM; Levy JR; Rader EP; Lueck JD; Bansal D; Moore SA; Ng R; Beltran-Valero de Bernabe D; Faulkner JA; Campbell KP. 2010. Genetic ablation of complement C3 attenuates muscle pathology in dysferlin-deficient mice. J Clin Invest 120(12):4366-74. [PubMed: 21060153]  [MGI Ref ID J:171870]

Han R; Rader EP; Levy JR; Bansal D; Campbell KP. 2011. Dystrophin deficiency exacerbates skeletal muscle pathology in dysferlin-null mice. Skelet Muscle 1(1):35. [PubMed: 22132688]  [MGI Ref ID J:183725]

Spector I; Zilberstein Y; Lavy A; Genin O; Barzilai-Tutsch H; Bodanovsky A; Halevy O; Pines M. 2013. The involvement of collagen triple helix repeat containing 1 in muscular dystrophies. Am J Pathol 182(3):905-16. [PubMed: 23274062]  [MGI Ref ID J:193271]

Turk R; Sterrenburg E; van der Wees CG; de Meijer EJ; de Menezes RX; Groh S; Campbell KP; Noguchi S; van Ommen GJ; den Dunnen JT; 't Hoen PA. 2006. Common pathological mechanisms in mouse models for muscular dystrophies. FASEB J 20(1):127-9. [PubMed: 16306063]  [MGI Ref ID J:104560]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX11

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, homozygotes or heterozygotes may be bred. Malocclusions may occur which require teeth clipping to allow normal eating and drinking.
Mating System	Homozygote x Homozygote         (Female x Male)   18-DEC-12
Diet Information	LabDiet® 5K52/5K67

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

Control Information

	Control
	000664 C57BL/6J
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

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Terms are granted by individual review and stated on the customer invoice(s) and account statement. These transactions are payable in U.S. currency within the granted terms. Payment for services, products, shipping containers, and shipping costs that are rendered are expected within the payment terms indicated on the invoice or stated by contract. Invoices and account balances in arrears of stated terms may result in The Jackson Laboratory pursuing collection activities including but not limited to outside agencies and court filings.

See Terms of Use tab for General Terms and Conditions

The Jackson Laboratory's Genotype Promise

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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