Strain Name:

FVB/N-Tg(ACTA1-TPM3*M9R)4Hrd/MbngJ

Stock Number:

018304

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HSA-αTmslow(Met9Arg) transgenic mice exhibit an overexpression of a dominant-negative alpha-tropomyosin slow Met9Arg mutation associated with human nemaline myopathy (NM) directed to fast-twitch glycolytic skeletal muscle (type 2B) fibers. Transgenic mice display features of NM in skeletal muscle tissue, including electron-dense accumulations (nemaline rods), increased slow/oxidative fiber content, and late-onset skeletal muscle weakness. These HSA-αTmslow(Met9Arg) transgenic mice may be useful in studying nemaline myopathy, skeletal muscle repair, and congenital muscular dystrophy.

Description

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Strain Information

Type Coisogenic; Mutant Strain; Transgenic;
Additional information on Genetically Engineered and Mutant Mice.
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Specieslaboratory mouse
Generation+pN1
Generation Definitions
 
Donating Investigator Marie-Louise Bang,   Istituto Clinico Humanitas IRGB-CNR
Donating Investigator Edna C Hardeman,   The University of New South Wales

Description
Human nemaline myopathy (NM) is a hereditary disease of skeletal muscle defined by a distinct pathology of electron-dense accumulations (rods) within the sarcomeric units. HSA-αTmslow(Met9Arg) transgenic mice express a human αTmslow cDNA sequence modified to have the dominant-negative Met9Arg mutation associated with NM, all under the direction of the 2.2 kbp human α-skeletal actin (ACTA1 or HSA) promoter. As expected for this HSA promoter, αTmslow(Met9Arg) expression is directed primarily to fast-twitch glycolytic skeletal muscle (type 2B) fibers in the transgenic mice.

The specific phenotype of hemizygous HSA-αTmslow(Met9Arg) transgenic mice from founder line 4 is described below.
HSA-αTmslow(Met9Arg) transgenic mice are viable and fertile, with αTmslow(Met9Arg) mRNA expression levels ~160% that of the endogenous αTmslow gene in slow fibers. Such overexpression of the dominant-negative Met9Arg mutant isoform in type 2B fibers results in clinical and pathological features of NM in multiple different skeletal muscles, including the presence of nemaline rods, increased slow/oxidative fiber content, and late-onset skeletal muscle weakness. As determined by immunofluorescent α-actinin 2 staining, nemaline rods are observed at the center and periphery of all fast glycolytic skeletal muscle (type 2B) fibers, and are commonly clustered around the Z-line of the sarcomere. The percentage of rods containing fibers increases between 2-12 months of age, and the percentage varies considerably between different muscles (but does not correlate with amount of mutant protein present). Transgenic mice exhibit a non-progressive increase in slow/fast oxidative fiber types 1 and 2A by ~2 months of age. Hypertrophy of type 2B fibers is apparent by ~2 months of age, but declines over the next 3-5 months. This age-related decline in hypertrophy correlates with late-onset muscle weakness beginning ~5-6 months of age, with muscle weakness progressing in severity out to 10-13 months of age. Like human nemaline disease, the muscle weakness in transgenic mice does not correlate with the numbers of rod-containing fibers or with the degree of type 1 fiber predominance. In contrast to human muscles, cytoplasmic bodies and tubular aggregates were observed in superficial gastrocnemius of transgenic mice (and not in any other mouse muscles examined). The hypertrophy of type 2B fibers observed in these mice may be sufficient to prevent overt muscle weakness in an unchallenged environment.

Regarding any differences between hemizygous and homozygous mice: The donating investigator (Dr. Edna C. Hardeman) maintained her transgenic colony by backcrossing with FVB/NJ wildtype mice (total of six generations by 2009). In their colony, while the level of transgene expression was increased in homozygous mice, they observed no significant differences in clinical pathology, breeding, or lifespan between hemizygous and homozygous mice.

Development
The HSA-αTmslow(Met9Arg) transgene was created by Dr. Edna C. Hardeman (University of New South Wales, Sydney, Australia). The human tropomyosin 3 gene was used to isolate a full-length αTmslow cDNA sequence. The isolated sequence was modified by site-directed mutagenesis to have the ATG->AGG base pair substitution encoding a methionine-to-arginine substitution at codon 9 (M9R); resulting in the dominant-negative αTmslow(Met9Arg) mutation associated with human nemaline myopathy. The mutant cDNA sequence was placed downstream of a 2.2 kbp human α-skeletal actin (ACTA1) promoter sequence, and upstream of a 1022 bp cassette containing the SV40 small t antigen intron and 3' untranslated region. The transgene was injected into fertilized FVB/NJ eggs, which were then transferred to pseudopregnant foster females (ARC/S). Founder mice were identified and bred to FVB/NJ mice to generate each founder line. Three founder lines developed nemaline rod pathology with αTmslow(Met9Arg) transcript expression levels in slow fibers of ~160% (line 4), ~120% (line 14) and ~70% (line 9) that of the endogenous αTmslow gene. HSA-αTmslow(Met9Arg) transgenic mice from founder line 4 were then backcrossed to FVB/NJ inbred mice for six generations. In 2009, frozen embryos were sent to Dr. Marie-Louise Bang (Dulbecco Telethon Institute IRGB-CNR, Milan, Italy). There, transgenic mice were additionally backcrossed four generations with FVB/NCrl mice, and then sent to The Jackson Laboratory Repository in 2012. Upon arrival, mutant mice were bred to FVB/NJ inbred mice (Stock No. 001800) for at least one generation to establish The Jackson Laboratory Repository colony.

Control Information

  Control
   Noncarrier
   001800 FVB/NJ
 
  Considerations for Choosing Controls

Related Strains

View Strains carrying other alleles of ACTA1     (15 strains)

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI
- Characteristics of this human disease are associated with transgenes and other mutation types in the mouse.
Nemaline Myopathy 1; NEM1
- Potential model based on transgenic expression of an ortholog of a human gene that is associated with this disease. Phenotypic similarity to the human disease has not been tested.
Myopathy, Congenital, with Fiber-Type Disproportion; CFTD   (TPM3)
View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI
      assigned by genotype

Tg(ACTA1-TPM3*M9R)4Hrd/0

        FVB/NJ-Tg(ACTA1-TPM3*M9R)4Hrd
  • muscle phenotype
  • abnormal muscle physiology
    • skinner fibers exhibit minor changes in response to strontium sensitivity compared with wild-type fibers   (MGI Ref ID J:67596)
    • muscle weakness
      • late onset   (MGI Ref ID J:67596)
    • myopathy
      • nemaline myopathy   (MGI Ref ID J:67596)
  • abnormal skeletal muscle morphology
    • mice exhibit an increase in the number of slow/fast oxidative fibers compared with wild-type mice   (MGI Ref ID J:67596)
    • abnormal skeletal muscle fiber morphology
      • mice develop nemaline rods in muscles resulting in Z line streaming and disruption of sarcomeric register   (MGI Ref ID J:67596)
      • mice develop cytoplasmic bodies and tubular aggregates of the sarcoplasmic reticulum   (MGI Ref ID J:67596)
      • the number of fibers containing rods and rod size is different in different muscles   (MGI Ref ID J:67596)
      • increased skeletal muscle fiber size
        • mice exhibit hypertrophy of fast, glycolytic fibers   (MGI Ref ID J:67596)
View Research Applications

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

Developmental Biology Research
Mesodermal Defects
      Myogenesis Defects

Neurobiology Research
Ataxia (Movement) Defects
Neuromuscular Defects

Genes & Alleles

Gene & Allele Information provided by MGI

 
Allele Symbol Tg(ACTA1-TPM3*M9R)4Hrd
Allele Name transgene insertion 4, Edna Hardeman
Allele Type Transgenic (random, expressed)
Common Name(s) HSA-TPM3*M9R; HSA-aTmslow(Met9Arg); HSA-aTmslow(Met9Arg); HSA-alphaTmslow(Met9Arg); HSA-alphaTmslow(Met9Arg); TPM3(Met9Arg);
Strain of OriginFVB/NJ
Expressed Gene TPM3, tropomyosin 3, human
Promoter ACTA1, actin, alpha 1, skeletal muscle, human
Molecular Note First, the human tropomyosin 3 gene was used to isolate a full-length alphaTmslow cDNA sequence. Next, the sequence was modified by site-directed mutagenesis to have the ATG-to-AGG base pair substitution encoding a methionine-to-arginine substitution at codon 9 (M9R); resulting in thedominant-negative alphaTmslow(Met9Arg) mutation associated with human nemaline myopathy. The mutant cDNA sequence was placed downstream of a 2.2 kbp human alpha-skeletal actin (ACTA1) promoter sequence, and upstream of a 1022 bp cassette containing the SV40 small t antigen intron and 3' untranslated region. Lines 4, 9 and 14 were generated with high, low and moderate expression levels, respectively. [MGI Ref ID J:67596]
 
 

Genotyping

Genotyping Information

Genotyping Protocols

Tg(ACTA1-TPM3*M9R)4Hrd,

SEPARATED MELT


Tg(ACTA1-TPM3*M9R)4Hrd, Melt Curve Analysis
Tg(ACTA1-TPM3*M9R)4Hrd, Separated PCR


Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Brennan KJ; Hardeman EC. 1993. Quantitative analysis of the human alpha-skeletal actin gene in transgenic mice. J Biol Chem 268(1):719-25. [PubMed: 7678010]  [MGI Ref ID J:131782]

Corbett MA; Robinson CS; Dunglison GF; Yang N; Joya JE; Stewart AW; Schnell C; Gunning PW; North KN; Hardeman EC. 2001. A mutation in alpha-tropomyosin(slow) affects muscle strength, maturation and hypertrophy in a mouse model for nemaline myopathy. Hum Mol Genet 10(4):317-28. [PubMed: 11157795]  [MGI Ref ID J:67596]

Sanoudou D; Corbett MA; Han M; Ghoddusi M; Nguyen MA; Vlahovich N; Hardeman EC; Beggs AH. 2006. Skeletal muscle repair in a mouse model of nemaline myopathy. Hum Mol Genet 15(17):2603-12. [PubMed: 16877500]  [MGI Ref ID J:114928]

Health & husbandry

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Health & Colony Maintenance Information

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200.

Colony Maintenance

Breeding & HusbandryWhen maintaining a live colony, hemizygous mice may be bred together, to wildtype (noncarrier) mice from the colony or to FVB/NJ inbred mice (Stock No. 001800).

Regarding any differences between hemizygous and homozygous mice: The donating investigator (Dr. Edna C. Hardeman) maintained her transgenic colony by backcrossing with FVB/NJ wildtype mice (total of six generations by 2009). In their colony, while the level of transgene expression was increased in homozygous mice, they observed no significant differences in clinical pathology, breeding, or lifespan between hemizygous and homozygous mice.

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls


Pricing for USA, Canada and Mexico shipping destinations View International Pricing

Cryopreserved

Cryopreserved Mice - Ready for Recovery

Price (US dollars $)
Cryorecovery* $3175.00
Animals Provided

At least two mice that carry the mutation (if it is a mutant strain) will be provided. Their genotypes may not reflect those discussed in the strain description. Please inquire for possible genotypes and see additional details below.

Standard Supply

Cryopreserved. Ready for recovery. Please refer to pricing and supply notes on the strain data sheet for further information.

Supply Notes

  • Cryorecovery - Standard.
    Progeny testing is not required.
    The average number of mice provided from recovery of our cryopreserved strains is 10. The total number of animals provided, their gender and genotype will vary. We will fulfill your order by providing at least two pair of mice, at least one animal of each pair carrying the mutation of interest. Please inquire if larger numbers of animals with specific genotype and genders are needed. Animals typically ship between 11 and 14 weeks from the date of your order. If a second cryorecovery is needed in order to provide the minimum number of animals, animals will ship within 25 weeks. IMPORTANT NOTE: The genotypes of animals provided may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation, or that discussed in the strain description. Please inquire about possible genotypes which will be recovered for this specific strain. The Jackson Laboratory cannot guarantee the reproductive success of mice shipped to your facility. If the mice are lost after the first three days (post-arrival) or do not produce progeny at your facility, a new order and fee will be necessary.

    Cryorecovery to establish a Dedicated Supply for greater quantities of mice
    Mice recovered can be used to establish a dedicated colony to contractually supply you mice according to your requirements. Price by quotation. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 (from U.S.A., Canada or Puerto Rico only) or 1-207-288-5845 (from any location).

Pricing for International shipping destinations View USA Canada and Mexico Pricing

Cryopreserved

Cryopreserved Mice - Ready for Recovery

Price (US dollars $)
Cryorecovery* $4127.50
Animals Provided

At least two mice that carry the mutation (if it is a mutant strain) will be provided. Their genotypes may not reflect those discussed in the strain description. Please inquire for possible genotypes and see additional details below.

Standard Supply

Cryopreserved. Ready for recovery. Please refer to pricing and supply notes on the strain data sheet for further information.

Supply Notes

  • Cryorecovery - Standard.
    Progeny testing is not required.
    The average number of mice provided from recovery of our cryopreserved strains is 10. The total number of animals provided, their gender and genotype will vary. We will fulfill your order by providing at least two pair of mice, at least one animal of each pair carrying the mutation of interest. Please inquire if larger numbers of animals with specific genotype and genders are needed. Animals typically ship between 11 and 14 weeks from the date of your order. If a second cryorecovery is needed in order to provide the minimum number of animals, animals will ship within 25 weeks. IMPORTANT NOTE: The genotypes of animals provided may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation, or that discussed in the strain description. Please inquire about possible genotypes which will be recovered for this specific strain. The Jackson Laboratory cannot guarantee the reproductive success of mice shipped to your facility. If the mice are lost after the first three days (post-arrival) or do not produce progeny at your facility, a new order and fee will be necessary.

    Cryorecovery to establish a Dedicated Supply for greater quantities of mice
    Mice recovered can be used to establish a dedicated colony to contractually supply you mice according to your requirements. Price by quotation. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 (from U.S.A., Canada or Puerto Rico only) or 1-207-288-5845 (from any location).

View USA Canada and Mexico Pricing View International Pricing

Standard Supply

Cryopreserved. Ready for recovery. Please refer to pricing and supply notes on the strain data sheet for further information.

Control Information

  Control
   Noncarrier
   001800 FVB/NJ
 
  Considerations for Choosing Controls
  Control Pricing Information for Genetically Engineered Mutant Strains.
 

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