Townes model mice carry several human hemoglobin knock-in genes replacing the endogenous mouse genes and may be useful in studying sickle cell disease.
Paul Schmidt, Children's Hospital Boston
Genetic Background | Generation |
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?+F5
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Allele Type | Gene Symbol | Gene Name |
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Targeted (Inserted expressed sequence, Humanized sequence) | Hbb | hemoglobin beta chain complex |
Allele Type | Gene Symbol | Gene Name |
---|---|---|
Targeted (Inserted expressed sequence, Humanized sequence) | Hba | hemoglobin alpha chain complex |
Allele Type | Gene Symbol | Gene Name |
---|---|---|
Targeted (Inserted expressed sequence, Humanized sequence) | Hbb | hemoglobin beta chain complex |
Starting at:
$255.00 Domestic price for female 4-week |
510.00 Domestic price for breeder pair |
In an attempt to offer alleles on well-characterized or multiple genetic backgrounds, alleles are frequently moved to a genetic background different from that on which an allele was first characterized. It should be noted that the phenotype of these C57BL/6J-congenic mice could vary from that originally described on a B6;129 genetic background (Stock No. 013071). We may modify the strain description if necessary as published results become available.
These mice harbor a combination of the following knock-in mutations:
1) the Hbatm1(HBA)Tow mutation (also called hα ; replaces the endogenous mouse α-globin with the human α-globin gene), which is necessary to form the hemoglobin heterotetramer in conjunction with:
2) the Hbbtm2(HBG1,HBB*)Tow mutation (also called -1400 γ-βS ; replaces the endogenous mouse major and minor &beta-globin with the human hemoglobin gamma (Aγ) gene and the human sickle cell hemoglobin beta (βS) gene),
3) the Hbbtm3(HBG1,HBB)Tow mutation (also called -383 γ-βA ; replacing the endogenous mouse major and minor β-globin with the human hemoglobin gamma (Aγ) gene and the human wildtype hemoglobin beta (βA) gene).
These mice harbor the hα (Hbatm1(HBA)Tow) targeted mutation, the -1400 γ-βS (Hbbtm2(HBG1,HBB*)Tow) targeted mutation, and/or the -383 γ-βA (Hbbtm3(HBG1,HBB)Tow) targeted mutation. These mice should not harbor any wildtype allele at the Hbb locus.
The Hbatm1(HBA)Tow targeted mutation (hα) was created by replacing the endogenous mouse α-globin gene with a human α-globin gene.
The Hbbtm2(HBG1,HBB*)Tow targeted mutation (-1400 γ-βS) was created by replacing the endogenous mouse major and minor β-globin genes with both the human Aγ gene (with 1400 bp of 5' flanking sequence) and the human βS-globin gene (-1400 γ-βS). The βS gene contains an A to T mutation in the sixth codon of the human β-globin gene (resulting in a glutamic acid to valine conversion) that has been linked to sickle cell disease.
The Hbbtm3(HBG1,HBB)Tow targeted mutation (-383 γ-βA) was created by designing a targeting construct with the human hemoglobin gamma (Aγ) gene with 383 bp of 5' flanking sequence, the human wildtype hemoglobin beta (βA) gene with 815 bp of 5' flanking sequence, and a loxP-flanked phosphoglycerase/Hygromycin (PGK/Hygro) selection cassette.
The -383 γ-βA targeting construct was electroporated into embryonic stem (ES) cells from knock-in sickle cell mice (homozygous for the hα targeted mutation and homozygous for the -1400 γ-βS targeted mutation). The -383 γ-βA construct contains 383 bp of 5' flanking sequence which is targeted to 1400 bp of 5' flanking sequence already present in the ES cells as part of the -1400 γ- βS allele. Different recombination events in this flanking region produced two ES cell clones; clone 2 harbored the -383 γ-βA replacement allele. This clone was then transiently transfected with a Cre expressing plasmid to delete the PGK/Hygro cassette, and then injected into recipient blastocysts. The resulting chimeric males were bred to females homozygous for hα and heterozygous for -1400 γ-βS. Offspring with the sickle cell corrected genotypes (homozygous for hα and heterozygous at the Hbb locus (-383 γ-βA/-1400 γ-βS)) were obtained. These mice were maintained on a mixed C57BL/6;129 genetic background by breeding together for many generations prior to sending to The Jackson Laboratory Repository as Stock No. 013071.
Dr Paul Schmidt, from Boston Children's Hospital, purchased some Stock No. 013071 mice and subsequently separated the three alleles in order to backcross the strain to C57BL/6J (Stock No. 000664). Each allele was bred to C57BL/6J for at least 10 generations before being bred back together in one strain. The C57BL/6J-congenic strain was sent to The Jackson Laboratory as Stock No. 027265.
Expressed Gene | HBG1, hemoglobin subunit gamma 1, human |
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Expressed Gene | HBB, hemoglobin subunit beta, human |
Site of Expression | |
Expressed Gene | HBA, hemoglobin, alpha, human |
Site of Expression | |
Expressed Gene | HBG1, hemoglobin subunit gamma 1, human |
Expressed Gene | HBB, hemoglobin subunit beta, human |
Site of Expression |
Allele Name | targeted mutation 2, Timothy Townes |
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Allele Type | Targeted (Inserted expressed sequence, Humanized sequence) |
Allele Synonym(s) | -1400-gamma-betaS; Hbbhbetas; Hbbtm2(HBB*)Tow; HbSS-Townes |
Gene Symbol and Name | Hbb, hemoglobin beta chain complex |
Gene Synonym(s) | |
Expressed Gene | HBG1, hemoglobin subunit gamma 1, human |
Expressed Gene | HBB, hemoglobin subunit beta, human |
Strain of Origin | Not Specified |
Chromosome | 7 |
Molecular Note | The major and minor beta chains were replaced with a construct made of a 5.66 kb fragment of the human gamma chain including 1400 bp of 5' flanking sequence and a 4.1 kb fragment of the sickle cell form of human HBB in ES cells already containing a replacement of Hba complex with human HBA, Hbatm1(HBA)Tow. Cre-mediated recombination removed the floxed hygro cassette. |
Allele Name | targeted mutation 1, Timothy Townes |
---|---|
Allele Type | Targeted (Inserted expressed sequence, Humanized sequence) |
Allele Synonym(s) | HbA; Hbahalpha |
Gene Symbol and Name | Hba, hemoglobin alpha chain complex |
Gene Synonym(s) | |
Expressed Gene | HBA, hemoglobin, alpha, human |
Strain of Origin | Not Specified |
Chromosome | 11 |
Molecular Note | The complex was replaced with human HBA. Details will be described elsewhere. |
Allele Name | targeted mutation 3, Timothy Townes |
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Allele Type | Targeted (Inserted expressed sequence, Humanized sequence) |
Allele Synonym(s) | -383 gamma-betaA; Hbbtm3(HBB)Tow |
Gene Symbol and Name | Hbb, hemoglobin beta chain complex |
Gene Synonym(s) | |
Expressed Gene | HBG1, hemoglobin subunit gamma 1, human |
Expressed Gene | HBB, hemoglobin subunit beta, human |
Strain of Origin | Not Specified |
Chromosome | 7 |
Molecular Note | In ES cells that were homozygous for Hbatm1(HBA)Tow and Hbbtm2(HBG1,HBB*)Tow the human gamma chain and beta chain containing the sickle cell mutation (an A to T transversion in the sixth codon) were replaced with the human gamma chain, beta chain (lacking the sickle cell mutation) and 383 bp of sequence flanking the gamma chain. Cre-mediated recombination removed the floxed hygro cassette. |
When maintaining a live colony, hα/hα::βA/βS females may be bred to hα/hα::βA/βS males or hα/hα::βA/βA males. These mice should never be bred with wildtype mice or the humanized genes may be lost.
In 2018, neither the donating laboratory nor The Jackson Laboratory had been able to generate C57BL/6J-congenic hα/hα::βS/βS live mice. Therefore, Stock No. 027265 is not viable as hα/hα::βS/βS.
When using the hα/hα::βA/βS mouse strain in a publication, please cite the originating article(s) and include JAX stock #027265 in your Materials and Methods section.
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