STOCK Hba^tm1Paz Hbb^tm1Tow Tg(HBA-HBBs)41Paz/J

Stock number: 003342
Product name: Berkeley model
Strain synonyms: sickle cell anemia
Research areas: Hematological Research, Mouse/Human Gene Homologs

Description

Mice homozygous for the alpha-globin null allele, homozygous for the beta-globin null allele and carrying the sickle transgene (Hba^0/0 Hbb^0/0 Tg(Hu-miniLCRα1^Gγ^Aγδβ^S) 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.

Detailed description

These mice harbor
1) the Hba^tm1Paz null mutation (also called Hba⁰ ; designed with both of the adult hemoglobin genes [α1 and α2] deleted),
2) the Hbb^tm1Tow 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-miniLCRα1^Gγ^Aγδβ^S); designed with the human sequences encoding the hemoglobin subunits alpha 1 (HBA1), gamma 2 (HBG2), gamma (HBG1), delta (HBD), and the beta sickle allele (HBB^S), 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 (Hba^0/0 Hbb^0/0 Tg(Hu-miniLCRα1^Gγ^Aγδβ^S) 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 Pde6b^rd1.

Development

The Hba^tm1Paz 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 Hbb^tm1Tow 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-miniLCRα1^Gγ^Aγδβ^S) 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 (HBB^S), as well as the locus control region (LCR). The HBB^S 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-miniLCRα1^Gγ^Aγδβ^S 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.

Allele

Symbol: Tg(HBA-HBBs)41Paz
Name: transgene insertion 41, Chris Paszty
MGI accession ID: MGI:3056733
Generation method: Transgenic
Attributes: Inserted expressed sequence; Humanized sequence
Marker symbol: Tg(HBA-HBBs)41Paz
Marker name: transgene insertion 41, Chris Paszty
Chromosome: UN
Strain of origin: FVB/N
Expressed genes: HBG2,hemoglobin subunit gamma 2,human; HBG1,hemoglobin subunit gamma 1,human; HBD,hemoglobin subunit delta,human; HBB,hemoglobin subunit beta,human; HBA1,hemoglobin subunit alpha 1,human
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 HBB^S 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.
General note: In conjunction with Hba^tm1Paz and Hbb^tm1Tmt, 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.

Allele

Symbol: Hbb^tm1Tow
Name: targeted mutation 1, Timothy Townes
MGI accession ID: MGI:2664239
Generation method: Targeted
Attributes: Null/Knockout
Marker symbol: Hbb
Marker name: hemoglobin beta chain complex
Chromosome: 7
Strain of origin: 129S2/SvPas
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.

Allele

Symbol: Hba^tm1Paz
Name: targeted mutation 1, Chris Paszty
MGI accession ID: MGI:2450531
Generation method: Targeted
Attributes: Null/Knockout
Marker symbol: Hba
Marker name: hemoglobin alpha chain complex
Chromosome: 11
Strain of origin: 129S7/SvEvBrd-Hprt1⁺
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.