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Strain Name:

STOCK Hbatm1Paz Hbbtm1Tow Tg(HBA-HBBs)41Paz/J

Stock Number:

003342

Availability:

Repository- Live

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Genes & Alleles   HBA1;   HBB;   HBD;   HBG1;   HBG2;   Hba;   Hbatm1Paz;   Hbb;   Hbbtm1Tow;   Tg(HBA-HBBs)41Paz;

Product Information

Strain Details

Type JAX® GEMM® Strain - Mutant Stock
Additional information on JAX® GEMM® Strains.
Type JAX® GEMM® Strain - Targeted Mutation
Type JAX® GEMM® Strain - Transgenic
Mating SystemSee Colony Maintenance         (Female x Male)
Specieslaboratory mouse
Donating Investigator Chris Paszty,   Amgen, Inc.
GenerationN1F7G12 (04-DEC-07)

Strain Description
This strain was engineered so that it no longer expresses mouse Hba and Hbb, but does express human HBA and HBB. It mimics the genetic, hematologic and histopathologic features that are found in humans afflicted with sickle cell anemia, including irreversibly sickled red blood cells, anemia and multiorgan pathology. A significant percentage of sickle cell mice do not survive to adulthood.

Strain Development
A transgenic construct containing human HBA1 (hemoglobin, alpha 1), HBG2 (hemoglobin, gamma G, fetal component), HBG1 (hemoglobin, gamma A, fetal component), HBD (hemoglobin, delta) and HBBS (hemoglobin, beta, sickle allele) genes and the locus control region were injected into fertilized FVB/N mouse eggs. Mice carrying the transgene were bred to mutant mice bearing targeted mutations in the endogenous mouse Hba and Hbb genes. The STOCK background of this strain is a mixture of FVB/N, 129, DBA/2, Black Swiss and >50% C57BL/6 genomes. It was backcrossed to C57BL/6J one generation after importation to The Jackson Laboratory.

Related Disease (OMIM) Terms

Sickle Cell Anemia
Mammalian Phenotype Terms assigned by genotype

Hbatm1Paz/Hbatm1Paz Hbbtm1Tow/Hbbtm1Tow Tg(HBA-HBBs)41Paz/?

        involves: 129S2/SvPas * 129S7/SvEvBrd * Black Swiss * C57BL/6 * DBA/2* FVB/N
  • lethality-prenatal/perinatal
  • neonatal lethality (MGI Ref ID J:44161)
    • many pups turn purple and die within a few hours of birth, however, mice that survive live to become adults (reaching at least 7 months of age)
  • hematopoietic system phenotype
  • abnormal erythrocyte morphology (MGI Ref ID J:44161)
    • erythrocytes have decreased osmotic fragility and increased dynamic rigidity
    • anisopoikilocytosis (MGI Ref ID J:44161)
      • sickle cell shapes are observed at a frequency of 5-10% in oxygenated blood
    • decreased mean corpuscular volume (MGI Ref ID J:44161)
  • abnormal reticulocyte morphology (MGI Ref ID J:44161)
    • reticulocyte counts are elevated at 3-7 months of age
  • anemia (MGI Ref ID J:44161)
  • decreased hematocrit (MGI Ref ID J:44161)
    • average hematocrit levels are 65% of control at 3-7 months of age
  • hemoglobin abnormalities (MGI Ref ID J:44161)
    • erythrocytes contain an excess of alpha globin chain synthesis
    • decreased mean corpuscular hemoglobin concentration (MGI Ref ID J:44161)
    • decreased mean corpuscular hemoglobin (MGI Ref ID J:44161)
  • increased spleen weight (MGI Ref ID J:44161)
    • weight is increased 13-fold as compared to control
  • homeostasis/metabolism phenotype
  • abnormal kidney iron level (MGI Ref ID J:44161)
    • iron deposits found in the tubular epithelium of the kidney
  • hypoxia (MGI Ref ID J:44161)
    • cause of death in some newborn mice
  • increased liver iron level (MGI Ref ID J:44161)
    • iron deposits found in Kupffer cells of liver
  • cardiovascular system phenotype
  • abnormal kidney vasculature (MGI Ref ID J:44161)
    • kidney infarction
  • increased heart weight (MGI Ref ID J:44161)
    • weight is increased 2-fold as compared to control
  • vasculature congestion (MGI Ref ID J:44161)
    • infarctions are observed in kidney, lungs and liver
    • congested sinusoidal channels are observed in spleen
  • renal/urinary system phenotype
  • abnormal kidney iron level (MGI Ref ID J:44161)
    • iron deposits found in the tubular epithelium of the kidney
  • abnormal kidney vasculature (MGI Ref ID J:44161)
    • kidney infarction
  • increased kidney weight (MGI Ref ID J:44161)
    • weight is increased 2-fold as compared to control
  • kidney atrophy (MGI Ref ID J:44161)
  • kidney cysts (MGI Ref ID J:44161)
  • renal fibrosis (MGI Ref ID J:44161)
  • immune system phenotype
  • increased spleen weight (MGI Ref ID J:44161)
    • weight is increased 13-fold as compared to control
  • liver/biliary system phenotype
  • increased liver iron level (MGI Ref ID J:44161)
    • iron deposits found in Kupffer cells of liver

Gene & Allele Details

Allele Symbol Hbatm1Paz
Allele Name targeted mutation 1, Chris Paszty
Common Name(s) Hba0; Hba1-2del;
Mutation Made By Chris Paszty,   Amgen, Inc.
Strain of Origin129S7/SvEvBrd-Hprt1<+>
ES Cell Line NameAB1
ES Cell Line Strain129S7/SvEvBrd-Hprt1<+>
Gene Symbol and Name Hba, hemoglobin alpha chain complex
Chromosome 11
Molecular Note Both of the adult hemoglobin genes, alpha 1 and alpha 2, and the region between them were deleted and replaced with a neomycin resistance cassette by homologous recombination. [MGI Ref ID J:28392]
 
Allele Symbol Hbbtm1Tow
Allele Name targeted mutation 1, Timothy Townes
Common Name(s) Hbb0; Hbbtm1Tmt;
Mutation Made By Timothy Townes,   University of Alabama School of Medicine
Strain of Origin129S2/SvPas
ES Cell Line NameD3
ES Cell Line Strain129S2/SvPas
Gene Symbol and Name Hbb, hemoglobin beta chain complex
Chromosome 7
Gene Common Name(s) CD113t-C; HBD;
General Note Homozygous mutant animals die in utero. Heterozygous mutant mice are fertile but are anemic and display abnormal red cell morphology, splenomegaly, and markedly increased reticulocyte counts.
Molecular Note A genomic fragment encompassing all of Hbb-b1 and a 5' portion of Hbb-b2 was replaced with a neo cassette inserted by homologous recombination. [MGI Ref ID J:29087]
 
Allele Symbol Tg(HBA-HBBs)41Paz
Allele Name transgene insertion 41, Chris Paszty
Common Name(s) BERK; Tg(Hu-miniLCRalpha1GgammaAgammadeltabetaS);
Mutation Made By Chris Paszty,   Amgen, Inc.
Strain of OriginFVB/N
Expressed Gene HBG1, hemoglobin, gamma A, human
Expressed Gene HBG2, hemoglobin, gamma G, human
Expressed Gene HBA1, hemoglobin, alpha 1, human
Expressed Gene HBB, hemoglobin, beta, human
Expressed Gene HBD, hemoglobin, delta, human
General Note In conjunction with Hbatm1Paz and Hbbtm1Tmt, transgenic mice express exclusively human sickle hemoglobin. These mice do not express mouse Hba and Hbb, but do express human HBA and HBB. Although chronically anemic, most of these mice survive for 2 to 9 months and are fertile. A significant percentage of sickle cell mice do not survive to adulthood. These mice display the major genetic, hematologic and histopathologic features found in humans with sickle cell disease: irreversibly sickled red cells, anemia, and multiorgan pathology.
Molecular Note The transgene contains sequences encoding the human proteins HBA1 (hemoglobin, alpha 1), HBG2 (hemoglobin, gamma G, fetal component), HBG1 (hemoglobin, gamma A, fetal component), HBD (hemoglobin, delta), and HBB S (hemoglobin, beta, sickle allele), and the locus control region (LCR). The HBBS allele contains an A to T transversion mutation in the sixth codon of HBB which causes an amino acid change from Glu to Val. The transgene promoter is multiple: from alpha and beta globin humanloci. Transgenic mice express human alpha hemoglobin, gamma hemoglobin, and sickle cell hemoglobin. [MGI Ref ID J:44161]

Control Information

  Control
   000664 C57BL/6J (approximate)
   Homozygous for Hbatm1Paz, Heterozygous for Hbbtm1Tow, Hemizygous for Tg(HBA-HBBs)41Paz (non-sickling females from the colony)
 
  Considerations for Choosing Controls

Genotyping Protocols

Hbatm1Paz
Hbbtm1Tow
Tg(HBA-HBBs)41Paz
Tg(HBA-HBBs)41Paz QPCR

Colony Maintenance

Breeding & HusbandryThe Hba and Hbb genes as well as the randomly-inserted transgene are not linked and thus will segregate independently. The breeding strategy utilized by The Jackson Laboratory follows a general scheme of mating non-sickling females with sickling males:

Type 1: homozygous for Hbatm1Paz, heterozygous for Hbbtm1Tow, carrying the transgene (-/-, +/-, Tg/?, non-sickling)
Type 2: homozygous for Hbatm1Paz, homozygous for Hbbtm1Tow, carrying the transgene (-/-, -/-, Tg/?, sickling)

Approximately 50% of progeny are homozygous for both Hba and Hbb targeted alleles and are hemizygous or homozygous for the transgene (sickling mutant mice). Of the sickling mutant mice, 81% will be hemizygous for the transgene and the other 19% will be homozygous. Only 40% of the sickling mutants will be male. Typically, ~20% of our sickling mutant mice die between weaning and 14 weeks. However, the 80% of mutants that survive beyond 14 weeks do not experience an abnormally high mortality rate. We are currently using trio matings with one male rotating among 4 pens to maximize colony breeding. Mutant females are not suitable for breeding, though we have been successful in transplanting mutant ovaries into immunodeficient recipients (e.g. NOD.CB17-Prkdcscid/J, stock number 001303). Mating female and male mice that are both homozygous for the transgene has not proven to be an effective mating scheme. Undersized litters result and only a small percentage of these are sickling mutant mice. Breeding units supplied to the customer will consist of one female (Type 1) and one male (Type 2). Hemizygosity (Tg/0) or homozygosity (Tg/Tg) of the transgene will be designated when animals are shipped. Due to the small yields of homozygotes and the small average litter size (~5 pups a litter), shipped breeding units may not consist of siblings. Type 2 (sickling) female mice can be obtained individually while Type 2 (sickling) male mutant mice will only be available as part of a breeding unit. Type 1 (non-sickling) females will be available as controls.
The STOCK background of this strain is a mixture of FVB/N, 129, DBA/2, Black Swiss and >50% C57BL/6 genomes. It was backcrossed to C57BL/6J one generation after importation to The Jackson Laboratory. Expected coat color from matings is black and agouti.

Diet Information LabDiet® 5K52/5K67

Related Strains

Strains carrying   Hbatm1Paz allele
002616   B6.129S7-Hbatm1Paz/J
View Strains carrying   Hbatm1Paz     (1 strain)

Strains carrying other alleles of Hba
001622   B6.CAST-Gpi1a.Cg-Hbath-J
000802   WB.Cg-Hbath-J/J
View Strains carrying other alleles of Hba     (2 strains)

View Strains carrying other alleles of Hbb     (11 strains)

Animal Health Reports

Room Number           AX12

Research Applications

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

Hematological Research
Sickle Cell Anemia

Hbatm1Paz related

Hematological Research
Hemoglobin Defects

Mouse/Human Gene Homologs
thalassemia, alpha

Hbbtm1Tow related

Hematological Research
Hemoglobin Defects

Mouse/Human Gene Homologs
thalassemia, beta

References

Selected Reference(s)

Paszty C; Brion CM; Manci E; Witkowska HE; Stevens ME; Mohandas N; Rubin EM. 1997. Transgenic knockout mice with exclusively human sickle hemoglobin and sickle cell disease [see comments] Science 278(5339):876-8. [PubMed: 9346488]  [MGI Ref ID J:44161]

Additional References

Price and Supply Information

Strain Name: STOCK Hbatm1Paz Hbbtm1Tow Tg(HBA-HBBs)41Paz/J
Stock Number: 003342

Price Details

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Supply Details

Standard SupplyRepository-Live. A collection of over 1000 strains maintained as live colonies. Individual colonies are sized to meet current customer demand. Delivery for orders of 10 mice or less ranges on average from one to eight weeks; mice are generally shipped between four to six weeks of age with a maximum shipping age of ~nine weeks. Colony sizes do not generally support stringent age specifications for large volumes of mice; however custom orders and larger quantities of mice are easily arranged. Estimated ship dates for all orders provided within 48 hours of order placement.
Supply Notes Usually shipped between four and eight weeks of age.
This strain is included in the Induced Mutant Resource Colony collection.
Genomic DNA is available for this strain from the Mouse DNA Resource.
LicensingSee General Terms and Conditions below for Licensing and Use Restrictions  
Control InformationView 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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