Mice homozygous for the alpha-globin null allele, homozygous for the beta-globin null allele and carrying the sickle transgene (Hba0/0 Hbb0/0 Tg(Hu-miniLCRα1GγAγδβS) are called sickle cell mice (Berkeley model). These mice display the major genetic, hematologic and histopathologic features observed in humans with sickle cell anemia and may be useful in studying sickle cell disease.
Dr. Chris Paszty, Amgen, Inc.
Genetic Background | Generation |
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N1F7G42
|
Allele Type | Gene Symbol | Gene Name |
---|---|---|
Targeted (Null/Knockout) | Hba | hemoglobin alpha chain complex |
Allele Type | Gene Symbol | Gene Name |
---|---|---|
Targeted (Null/Knockout) | Hbb | hemoglobin beta chain complex |
Allele Type |
---|
Transgenic (Inserted expressed sequence, Humanized sequence) |
Starting at:
$333.00 Domestic price for female 4-week |
666.00 Domestic price for breeder pair |
These mice harbor
1) the Hbatm1Paz null mutation (also called Hba0 ; designed with both of the adult hemoglobin genes [α1 and α2] deleted),
2) the Hbbtm1Tow null mutation (also called Hbb0 ; designed with deletion of the entire hemoglobin beta-β1 [major] and the 5’ portion of the hemoglobin beta-β2 [minor]),
3) the Tg(HBA-HBBs)41Paz transgene (also called Tg(Hu-miniLCRα1GγAγδβS); designed with the human sequences encoding the hemoglobin subunits alpha 1 (HBA1), gamma 2 (HBG2), gamma (HBG1), delta (HBD), and the beta sickle allele (HBBS), and the locus control region (LCR).
Mice homozygous for the alpha-globin null allele, homozygous for the beta-globin null allele and carrying the sickle transgene (Hba0/0 Hbb0/0 Tg(Hu-miniLCRα1GγAγδβS) are called sickle cell mice (Berkeley model). They exclusively express human sickle hemoglobin, and do not express mouse Hba or 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 observed in humans with sickle cell anemia; including irreversibly sickled red blood cells, anemia and multiorgan pathology. Typically, ~20% of sickling mutant mice die between weaning and 14 weeks of age.
This strain does not carry the retinal degeneration allele Pde6brd1.
The Hbatm1Paz null mutation (also called Hba0) was designed by Dr. Chris Paszty to have both of the endogenous adult hemoglobin genes (α1 and α2) deleted and replaced with a neo cassette.
The Hbbtm1Tow null mutation (also called Hbb0) was designed by Dr. Timothy Townes to have the endogenous hemoglobin beta sequences (the entire hemoglobin beta-β1 [major] and the 5' portion of the hemoglobin beta-β2 [minor]) deleted and replaced with a neo cassette.
The Tg(HBA-HBBs)41Paz transgene (also called Tg(Hu-miniLCRα1GγAγδβS) was designed by Dr. Chris Paszty to have sequences encoding the human hemoglobin subunits
alpha 1 (HBA1),
gamma 2 (HBG2),
gamma (HBG1),
delta (HBD),
and the beta sickle allele (HBBS), as well as the locus control region (LCR).
The HBBS sequence contains an A-to-T transversion mutation in HBB codon six (amino acid change from glutamic acid to valine; E6V). The transgene promoter is multiple; from alpha and beta globin human loci. The transgene was injected into fertilized FVB/N mouse eggs.
Breeding the above mice together created the triple mutant mice - Tg(Hu-miniLCRα1GγAγδβS Hba0 Hbb0. The STOCK background of the triple mutant 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.
Expressed Gene | HBG1, hemoglobin subunit gamma 1, human |
---|---|
Expressed Gene | HBG2, hemoglobin subunit gamma 2, human |
Expressed Gene | HBA1, hemoglobin subunit alpha 1, human |
Expressed Gene | HBB, hemoglobin subunit beta, human |
Expressed Gene | HBD, hemoglobin subunit delta, human |
Site of Expression |
Allele Name | targeted mutation 1, Chris Paszty |
---|---|
Allele Type | Targeted (Null/Knockout) |
Allele Synonym(s) | Hba0; Hba1-2del |
Gene Symbol and Name | Hba, hemoglobin alpha chain complex |
Gene Synonym(s) | |
Strain of Origin | 129S7/SvEvBrd-Hprt+ |
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. |
Mutations Made By | Dr. Chris Paszty, Amgen, Inc. |
Allele Name | targeted mutation 1, Timothy Townes |
---|---|
Allele Type | Targeted (Null/Knockout) |
Allele Synonym(s) | Hbb0; Hbbth3; Hbbtm1Tmt |
Gene Symbol and Name | Hbb, hemoglobin beta chain complex |
Gene Synonym(s) | |
Strain of Origin | 129S2/SvPas |
Chromosome | 7 |
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. |
Mutations Made By | Timothy Townes, University of Alabama School of Medicine |
Allele Name | transgene insertion 41, Chris Paszty |
---|---|
Allele Type | Transgenic (Inserted expressed sequence, Humanized sequence) |
Allele Synonym(s) | miniLCRalpha1GgammaAgammadeltabetaS; Tg(Hu-miniLCRalpha1GgammaAgammadeltabetaS) |
Gene Symbol and Name | Tg(HBA-HBBs)41Paz, transgene insertion 41, Chris Paszty |
Gene Synonym(s) | |
Promoter | HBA1, hemoglobin subunit alpha 1, human |
Promoter | HBB, hemoglobin subunit beta, human |
Expressed Gene | HBG1, hemoglobin subunit gamma 1, human |
Expressed Gene | HBG2, hemoglobin subunit gamma 2, human |
Expressed Gene | HBA1, hemoglobin subunit alpha 1, human |
Expressed Gene | HBB, hemoglobin subunit beta, human |
Expressed Gene | HBD, hemoglobin subunit delta, human |
Strain of Origin | FVB/N |
Chromosome | UN |
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 human loci. Transgenic mice express human alpha hemoglobin, gamma hemoglobin, and sickle cell hemoglobin. |
Mutations Made By | Dr. Chris Paszty, Amgen, Inc. |
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, hemizygous for Tg(HBA-HBBs)41Paz (-/-, +/-, Tg/0, non-sickling)
Type 2:
homozygous for Hbatm1Paz, homozygous for Hbbtm1Tow, homozygous for Tg(HBA-HBBs)41Paz (-/-, -/-, Tg/Tg, sickling)
Currently, trio matings are being used to maximize colony breeding. Sickling females are not suitable for breeding. 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 these 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 sickling mutant mice die between weaning and 14 weeks of age.
Breeding units supplied to the customer will consist of one non-sickling female (Type 1 [-/-, +/-, Tg/0]) and one sickling male (homozygous for Hbatm1Paz, homozygous for Hbbtm1Tow, hemizygous for Tg(HBA-HBBs)41Paz [-/-, -/-, Tg/0]).
The Jackson Laboratory does not offer triple homozygous males or females because they do not survive shipping.
Mating mice that are both homozygous for the transgene results in undersized litters and a small percentage of sickling pups.
When using the Berkeley model mouse strain in a publication, please cite the originating article(s) and include JAX stock #003342 in your Materials and Methods section.
Service/Product | Description | Price |
---|---|---|
Homozygous for Hba<tm1Paz>, Heterozygous for Hbb<tm1Tow>, Hemizygous or Homozygous for Tg(HBA-HBBs)41Paz |
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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. We do not guarantee breeding performance and therefore suggest that investigators order more than one breeding pair to avoid delays in their research.
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