Overview

Also Known As:sickle cell anemia, Berkeley model

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.

Donating Investigator

Dr. Chris Paszty, Amgen, Inc.

Genetic overview

Genetic Background	Generation
	N1F7G42 (2021-01-09 00:00:00)

Hba^tm1Paz

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Hba	hemoglobin alpha chain complex

Hbb^tm1Tow

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Hbb	hemoglobin beta chain complex

Tg(HBA-HBBs)41Paz

Allele Type
Transgenic (Inserted expressed sequence, Humanized sequence)

View Genetics

Research Applications

Hematological Research
Mouse/Human Gene Homologs

View All Research Applications

Base Price

Starting at:

$333.00 Domestic price for female 4-week

666.00 Domestic price for breeder pair

View Price List

Details

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.

Expression Data

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

Control Suggestions

Homozygous for Hba^tm1Paz, Heterozygous for Hbb^tm1Tow, Hemizygous for Tg(HBA-HBBs)41Paz (non-sickling mice from the colony)

Approximate Controls

000664 C57BL/6J

Additional Information

Considerations for Choosing Controls

Selected References

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):876-8PubMed: 9346488 MGI: J:44161

View All References

Genetics

Hba^tm1Paz

Allele Symbol: Hba^tm1Paz

Allele Name	targeted mutation 1, Chris Paszty
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	Hba⁰; Hba^1-2del
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.

Hbb^tm1Tow

Allele Symbol: Hbb^tm1Tow

Allele Name	targeted mutation 1, Timothy Townes
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	Hbb⁰; Hbb^th3; Hbb^tm1Tmt
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

Tg(HBA-HBBs)41Paz

Allele Symbol: Tg(HBA-HBBs)41Paz

Allele Name	transgene insertion 41, Chris Paszty
Allele Type	Transgenic (Inserted expressed sequence, Humanized sequence)
Allele Synonym(s)	miniLCRalpha1^Ggamma^Agammadeltabeta^S; Tg(Hu-miniLCRalpha1^Ggamma^Agammadeltabeta^S)
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 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.
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.
Mutations Made By	Dr. Chris Paszty, Amgen, Inc.

Disease/Phenotype

Disease Terms

Characteristics of this human disease are associated with transgenes and other mutation types in the mouse.

sickle cell anemia

Research Areas By Phenotype

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

Hematological Research
- Sickle Cell Anemia

Genotype: Hba^tm1Paz related

Hematological Research
- Hemoglobin Defects
Mouse/Human Gene Homologs
- thalassemia, alpha

Genotype: Hbb^tm1Tow related

Hematological Research
- Hemoglobin Defects
Mouse/Human Gene Homologs
- thalassemia, beta

Mammalian Phenotype Terms by Genotype

The following phenotype relates to a compound genotype created using this strain

Genotype: Hba^tm1Paz/Hba^tm1Paz Hbb^tm1Tow/Hbb^tm1Tow Tg(HBA-HBBs)41Paz/0
involves: 129 * Black Swiss * C57BL/6 * DBA/2 * FVB/N

reproductive system phenotype

abnormal penile erection
- Normal - however, treatment with an Adora2b antagonist or PEG-ADA reduces priapic activity
- mice exhibit increased corpus cavernosal smooth muscle relaxation in response to nerve stimulation

priapism
- Normal - however, treatment with an Adora2b antagonist or PEG-ADA reduces priapic activity
- mice exhibit priapism that is associated with elevated levels of adenosine

Genotype: Hba^tm1Paz/Hba^tm1Paz Hbb^tm1Tow/Hbb^tm1Tow Tg(HBA-HBBs)41Paz/?
involves: 129S2/SvPas * 129S7/SvEvBrd * Black Swiss * C57BL/6 * DBA/2* FVB/N

hematopoietic system phenotype

decreased erythrocyte osmotic fragility
- erythrocytes have decreased osmotic fragility

decreased hematocrit
- average hematocrit levels are 65% of control at 3-7 months of age

decreased mean corpuscular volume

spleen vascular congestion
- congested sinusoidal channels are observed in spleen

reticulocytosis
- reticulocyte counts are elevated at 3-7 months of age

abnormal hemoglobin
- erythrocytes contain an excess of alpha globin chain synthesis

increased spleen weight
- weight is increased 13-fold as compared to control

decreased mean corpuscular hemoglobin

anemia

abnormal erythrocyte morphology
- erythrocytes have increased dynamic rigidity

abnormal erythrocyte osmotic lysis
- erythrocytes have decreased osmotic fragility

decreased mean corpuscular hemoglobin concentration

anisopoikilocytosis
- sickle cell shapes are observed at a frequency of 5-10% in oxygenated blood

homeostasis/metabolism phenotype

increased kidney iron level
- iron deposits found in the tubular epithelium of the kidney

hypoxia
- cause of death in some newborn mice

increased liver iron level
- iron deposits found in Kupffer cells of liver

immune system phenotype

increased spleen weight
- weight is increased 13-fold as compared to control

spleen vascular congestion
- congested sinusoidal channels are observed in spleen

liver/biliary system phenotype

increased liver iron level
- iron deposits found in Kupffer cells of liver

abnormal liver vasculature morphology
- liver infarction

mortality/aging

neonatal lethality, incomplete penetrance
- 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)

renal/urinary system phenotype

kidney atrophy

kidney cysts

increased kidney iron level
- iron deposits found in the tubular epithelium of the kidney

renal fibrosis

increased kidney weight
- weight is increased 2-fold as compared to control

abnormal kidney blood vessel morphology
- kidney infarction

respiratory system phenotype

abnormal lung vasculature morphology
- lung infarction

cardiovascular system phenotype

spleen vascular congestion
- congested sinusoidal channels are observed in spleen

abnormal kidney blood vessel morphology
- kidney infarction

abnormal liver vasculature morphology
- liver infarction

abnormal lung vasculature morphology
- lung infarction

increased heart weight
- weight is increased 2-fold as compared to control

growth/size/body region phenotype

increased kidney weight
- weight is increased 2-fold as compared to control

increased spleen weight
- weight is increased 13-fold as compared to control

increased heart weight
- weight is increased 2-fold as compared to control

References

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):876-8PubMed: 9346488 MGI: J:44161

Additional References

Barinaga M. 1997. Mutant mice mimic human sickle cell anemia [news; comment] Science 278(5339):803-4PubMed: 9381190 MGI: J:44159
Ciavatta DJ; Ryan TM; Farmer SC; Townes TM. 1995. Mouse model of human beta zero thalassemia: targeted deletion of the mouse beta maj- and beta min-globin genes in embryonic stem cells. Proc Natl Acad Sci U S A 92(20):9259-63PubMed: 7568113 MGI: J:29087
Ryan TM; Ciavatta DJ; Townes TM. 1997. Knockout-transgenic mouse model of sickle cell disease [see comments] Science 278(5339):873-6PubMed: 9346487 MGI: J:44160

Additional - Hba^tm1Paz related

Additional - Hbb^tm1Tow related

Additional - Tg(HBA-HBBs)41Paz related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- End Point Analysis:Hbb-PROBE
- Separated PCR:Hbbalternate3
- Standard PCR:Hba Alternate2
- Standard PCR:Tg(HBA-HBBs)41Paz
- QPCR:Tg(HBA-HBBs)41Paz
- QPCR:Tg(HBA-HBBs)41Paz
- Probe:Hba Probe
- Probe:Pde6b Probe
- Genotyping resources and troubleshooting
Dietary Information
- LabDiet® 5K52 formulation (6% fat)
Breeding Considerations

The breeding strategy utilized by The Jackson Laboratory follows a general scheme of mating non-sickling females with sickling males:

Type 1:
homozygous for Hba^tm1Paz, heterozygous for Hbb^tm1Tow, hemizygous for Tg(HBA-HBBs)41Paz (-/-, +/-, Tg/0, non-sickling)

Type 2:
homozygous for Hba^tm1Paz, homozygous for Hbb^tm1Tow, 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 Hba^tm1Paz, homozygous for Hbb^tm1Tow, 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.
- Additional Breeding and Husbandry Support
Mating System
- HOM HET HEMI X HOM HOM HOM (NO RECIP)
Appearance
- Expected coat color from matings is black and agouti.
Citation
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.

Animal Health Reports

Facility Barrier Level Descriptions

AX11 (Maximum)

Pricing & Availability

Available

Domestic
International

Live Mouse

Age

Genotype

Price

weeks

Breeder Pair

Sex

Genotype

Price

Female
Male

Cryorecovery - Pricing

Service/Product	Description	Price
	Homozygous for Hba<tm1Paz>, Heterozygous for Hbb<tm1Tow>, Hemizygous or Homozygous for Tg(HBA-HBBs)41Paz

Payment Terms and Conditions

Terms are granted by individual review and stated on the customer invoice(s) and account statement. These transactions are payable in U.S. currency within the granted terms. Payment for services, products, shipping containers, and shipping costs that are rendered are expected within the payment terms indicated on the invoice or stated by contract. Invoices and account balances in arrears of stated terms may result in The Jackson Laboratory pursuing collection activities including but not limited to outside agencies and court filings.

The Jackson Laboratory's Genotype Promise

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.

Terms Of Use

General Terms and Conditions

Questions about Terms of Use

Additional Use Restrictions Apply

Use of MICE by companies or for-profit entities requires a license prior to shipping.

Licensing Information

Phone: 207-288-6470

Email: TechTran@jax.org

Also Known As:sickle cell anemia, Berkeley model

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Expression Data

Control Suggestions

Approximate Controls

Additional Information

Selected References

Hbatm1Paz

Allele Symbol: Hbatm1Paz

Hbbtm1Tow

Allele Symbol: Hbbtm1Tow

Tg(HBA-HBBs)41Paz

Allele Symbol: Tg(HBA-HBBs)41Paz

Disease Terms

Characteristics of this human disease are associated with transgenes and other mutation types in the mouse.

Research Areas By Phenotype

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

Genotype: Hbatm1Paz related

Genotype: Hbbtm1Tow related

Mammalian Phenotype Terms by Genotype

Genotype: Hbatm1Paz/Hbatm1Paz Hbbtm1Tow/Hbbtm1Tow Tg(HBA-HBBs)41Paz/0involves: 129 * Black Swiss * C57BL/6 * DBA/2 * FVB/N

reproductive system phenotype

Genotype: Hbatm1Paz/Hbatm1Paz Hbbtm1Tow/Hbbtm1Tow Tg(HBA-HBBs)41Paz/?involves: 129S2/SvPas * 129S7/SvEvBrd * Black Swiss * C57BL/6 * DBA/2* FVB/N

hematopoietic system phenotype

homeostasis/metabolism phenotype

immune system phenotype

liver/biliary system phenotype

mortality/aging

renal/urinary system phenotype

respiratory system phenotype

cardiovascular system phenotype

growth/size/body region phenotype

References

Additional References

Additional - Hbatm1Paz related

Additional - Hbbtm1Tow related

Additional - Tg(HBA-HBBs)41Paz related

Genotyping Protocols

Dietary Information

Breeding Considerations

Mating System

Appearance

Citation

Animal Health Reports

Live Mouse

Breeder Pair

Cryorecovery - Pricing

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms Of Use

Additional Use Restrictions Apply

Licensing Information

Hba^tm1Paz

Allele Symbol: Hba^tm1Paz

Hbb^tm1Tow

Allele Symbol: Hbb^tm1Tow

Genotype: Hba^tm1Paz related

Genotype: Hbb^tm1Tow related

Genotype: Hba^tm1Paz/Hba^tm1Paz Hbb^tm1Tow/Hbb^tm1Tow Tg(HBA-HBBs)41Paz/0
involves: 129 * Black Swiss * C57BL/6 * DBA/2 * FVB/N

Genotype: Hba^tm1Paz/Hba^tm1Paz Hbb^tm1Tow/Hbb^tm1Tow Tg(HBA-HBBs)41Paz/?
involves: 129S2/SvPas * 129S7/SvEvBrd * Black Swiss * C57BL/6 * DBA/2* FVB/N

Additional - Hba^tm1Paz related

Additional - Hbb^tm1Tow related