STOCK Hbb^d3th Tg(LCR-HBA1,LCR-HBB*)1Tow/J

Stock number: 021452
Research areas: Hematological Research, Internal/Organ Research

Description

These mice may be useful in studying sickle cell disease.

Detailed description

These mice harbor several mutations:
1) the Tg(LCRHBA1,LCRHBB)1Tow mutation (also called Hb S) designed with expression of the human hemoglobin beta chain complex (HBB) and human α1 globin (HBA1) being controlled independently by five upstream sites (HS I-V) of the human β-globin locus control regions (LCR). The HS I-V beta^S transgene expresses a glutamic acid to valine mutation of the human hemoglobin beta chain complex (HBB) that has been linked to Sickle Cell Disease.
as well as
2) the Hbb^d3th mutation (also called β^major) containing a spontaneous deletion of endogenous Hbb gene.

Hb S mice were bred to Hbb^d3th mice to increase expression of human β-globins in Hb S/β-thal mice. Hb S and Hb S/β-thal mice contain three and five times the level of endogenous mouse β-globin mRNA, respectively. They contain equivalent amounts of human α- and endogenous mouse α-globin mRNA. The donating investigator maintains the Hb S/β-thal mice by breeding mice heterozygous for the β-thal mutation and carrying one transgene copy. Mice homozygous for the β-thal mutation and homozygous for the transgene are viable.

Both groups exhibit decreased red blood cell counts and Hb concentrations. Reticulocyte counts are increased in Hb S/β-thal mice, indicating that they are mildly anemic. The spleens of Hb S/β-thal mice are two to four times larger than control spleens, as seen in children with sickle cell disease. Hypoxia (5% O2), causes the percentage of circulating sickled cells in the blood to increase, and leads to death from sickling-dependent pulmonary sequestration within 15 minutes.

Development

Two transgenes were designed to each be controlled independently by five upstream sites (HS I-V) of the human β-globin locus control regions (LCR). The HS I-V beta^S transgene expresses a glutamic acid to valine mutation of the human hemoglobin beta chain complex (HBB) that has been linked to sickle cell disease. The HS I-V alpha transgene expresses a human α1 globin (HBA1) gene. These constructs were coinjected into fertilized (C57BL/6 x SJL)F1 oocytes and insertion of the transgenes occured at a single locus. Founder mice, containing 5 copies of alpha and 7 copies of beta^S, were obtained and bred to C57BL/6J mice. The resulting colony of Hb S mice was maintained by crossing transgenic mice to C57BL/6 mice.

Hb S mice were bred to Hbb^d3th mice containing a spontaneous deletion of the endogenous Hbb gene(β^major) which had been backcrossed to C57BL/6J. These Hb S/β-thal mice were maintained on a mixed background. Upon arrival at The Jackson Laboratory, these mice were bred to C57BL/6J mice (Stock No. 000664) for at least one generation to establish the colony.

Allele

Symbol: Hbb^d3th
Name: beta-thalassemia
MGI accession ID: MGI:1856047
Generation method: Spontaneous
Marker symbol: Hbb
Marker name: hemoglobin beta chain complex
Chromosome: 7
Strain of origin: DBA/2J
Molecular note: A 3.7 kb region, including the entire beta major globin gene and 2 kilobases of 5' flanking region, is deleted. A novel approximately 66 bp sequence ending in a poly(A) stretch was found to bridge the deletion.

Allele

Symbol: Tg(LCR-HBA1,LCR-HBB*)1Tow
Name: transgene insertion 1, Timothy Townes
MGI accession ID: MGI:5484766
Generation method: Transgenic
Attributes: Inserted expressed sequence; Humanized sequence
Marker symbol: Tg(LCR-HBA1,LCR-HBB*)1Tow
Marker name: transgene insertion 1, Timothy Townes
Chromosome: UN
Strain of origin: (C57BL/6 x SJL)F1
Expressed genes: HBA1,hemoglobin subunit alpha 1,human; HBB,hemoglobin subunit beta,human
Molecular note: Two transgenes were designed to each be controlled independently by five upstream sites (HS I-V) of the human beta-globin locus control regions (LCR). The HS I-V betaS transgene expresses a glutamic acid to valine mutation of the human hemoglobin beta chain complex (HBB) that has been linked to sickle cell disease. The HS I-V alpha transgene expresses a human alpha1 globin (HBA1) gene. Line 1 was generated.