Description

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Strain Information

Type Congenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Additional information on Congenic nomenclature. Species laboratory mouse   Donating Investigator Jeffrey A. Frelinger,   Univ. North Carolina

Description
Mice that are homozygous for this targeted mutation are viable, fertile and normal in size. As this mutation is X-linked, males bearing the targeted allele display a mutant phenotype similar to that seen in homozygous females. Gene product activity, as measured by clotting activity using an activated partial thromboplastin time (APTT) Factor IX assay, was reduced to 8% of normal. Mutant mice experience spontaneous bleeding that can lead to swelling of the top of the feet or the footpads. Sudden death due to massive internal hemorrhaging can occur as a result of normal fighting in the cage. Tail cut wounds must be cauterized to prevent blood loss and death in mutant mice. This mutant mouse strain represents a model that may be useful in studies related to gene therapy methods and function of factor IX mutations.

Development
A targeting vector containing a neomycin resistance gene, herpes simplex virus thymidine kinase gene and a hypoxanthine phosphoribosyl transferase minigene (partially deleted and nonfunctional) was used to disrupt exons 1-3 of the targeted gene. The construct was electroporated into 129P2/OlaHsd derived E14TG2a embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 blastocysts. The resulting male chimeric animals were backcrossed to C57BL/6J mice.

Control Information

	Control
	000664 C57BL/6J
Considerations for Choosing Controls

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI

- Model with phenotypic similarity to human disease where etiologies involve orthologs. Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

Hemophilia B; HEMB

- Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested. Coumarin Resistance   (F9) Thrombophilia, X-Linked, Due to Factor IX Defect; THPH8   (F9)

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

The following phenotype information may relate to a genetic background differing from this JAX^® Mice strain.

F9^tm1Dws/F9^tm1Dws

        involves: 129P2/OlaHsd

• mortality/aging
• increased sensitivity to induced morbidity/mortality
  • rebleeding in 4 of 9 mice results in immobility and cardiovascular instability requiring euthanasia after less than 2 hours of observation   (MGI Ref ID J:166332)
• homeostasis/metabolism phenotype
• abnormal blood coagulation
  • rebleeding in 4 of 9 mice results in immobility and cardiovascular instability requiring euthanasia after less than 2 hours of observation   (MGI Ref ID J:166332)
• • increased bleeding time
    • mice bleed for more than 10 minutes with a secondary bleeding challenge compared with 2.7 minutes for similarly treated wild-type mice   (MGI Ref ID J:166332)
• hematopoietic system phenotype
• decreased hematocrit
  • following bleeding experiments   (MGI Ref ID J:166332)

F9^tm1Dws/Y

        involves: 129P2/OlaHsd * C57BL/6

• mortality/aging
• premature death
  • male hemizygotes survive well if no injury occurs but occasionally exhibit sudden death during growth, mostly as a result of internal hemorrhage after normal fighting with littermates   (MGI Ref ID J:44497)
• homeostasis/metabolism phenotype
• abnormal blood coagulation
  • male hemizygotes display a severe hemophilia B phenotype with reduced plasma clotting activity although an 8% residual activity is observed   (MGI Ref ID J:44497)
  • when their tails are cut, male hemizygotes bleed and die if the wound is not cauterized   (MGI Ref ID J:44497)
• cardiovascular system phenotype
• *normal* cardiovascular system phenotype
  • at 13 weeks of age, prohemorrhagic male hemizygotes display normal hearts with no evidence of hemosiderin deposition   (MGI Ref ID J:80537)
• • hemorrhage
    • male hemizygotes are grossly normal but display spontaneous bleeding, as shown by hemorrhagic swelling of the top of the feet or of the footpads or the presence of pale footpads   (MGI Ref ID J:44497)
    • at autopsy, male hemizygotes show massive hemorrhages, mostly subcutaneous or in the dorsal surface musculature   (MGI Ref ID J:44497)
    • intra-cranial hemorrhages, hemorrhages in the axilliary and inguinal areas, hemorrhages around the salivary glands, and hemorrhages in the pericardium are also observed   (MGI Ref ID J:44497)
  • • internal hemorrhage
      • male hemizygotes display fatal internal hemorrhage after normal fighting with littermates   (MGI Ref ID J:44497)
• hematopoietic system phenotype
• enlarged spleen
  • male hemizygotes commonly exhibit splenomegaly, indicating anemia caused by blood loss   (MGI Ref ID J:44497)
• immune system phenotype
• enlarged spleen
  • male hemizygotes commonly exhibit splenomegaly, indicating anemia caused by blood loss   (MGI Ref ID J:44497)

F9^tm1Dws/Y

        involves: 129P2/OlaHsd

• mortality/aging
• increased sensitivity to induced morbidity/mortality
  • rebleeding in 4 of 9 mice results in immobility and cardiovascular instability requiring euthanasia after less than 2 hours of observation   (MGI Ref ID J:166332)
• homeostasis/metabolism phenotype
• abnormal blood coagulation
  • rebleeding in 4 of 9 mice results in immobility and cardiovascular instability requiring euthanasia after less than 2 hours of observation   (MGI Ref ID J:166332)
• • increased bleeding time
    • mice bleed for more than 10 minutes with a secondary bleeding challenge compared with 2.7 minutes for similarly treated wild-type mice   (MGI Ref ID J:166332)
• hematopoietic system phenotype
• decreased hematocrit
  • following bleeding experiments   (MGI Ref ID J:166332)

View Research Applications

Research Applications

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

F9^tm1Dws related

Hematological Research
Clotting Defects

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		F9tm1Dws
Allele Name		targeted mutation 1, Darrel W Stafford
Allele Type		Targeted (knock-out)
Common Name(s)		FIX(-); HB; factor IX-knockout;
Mutation Made By		Jeffrey Frelinger,   Univ. North Carolina
Strain of Origin		129P2/OlaHsd
ES Cell Line Name		E14TG2a
ES Cell Line Strain		129P2/OlaHsd
Gene Symbol and Name		F9, coagulation factor IX
Chromosome		X
Gene Common Name(s)		AW111646; Cf-9; Cf9; FIX; HEMB; P19; PTC; THPH8; expressed sequence AW111646;
Molecular Note		Exons 1, 2 and 3 are replaced by a neomycin/hprt minigene cassette. No mRNA was detected in hemizygous male mice as assayed by RT-PCR analysis. [MGI Ref ID J:44497]

Genotyping

Genotyping Information

Genotyping Protocols

F9^tm1Dws redesign, Fast MCA
F9^tm1Dws redesign, Separated PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Lin HF; Maeda N; Smithies O; Straight DL; Stafford DW. 1997. A coagulation factor IX-deficient mouse model for human hemophilia B. Blood 90(10):3962-6. [PubMed: 9354664]  [MGI Ref ID J:44497]

Additional References

F9^tm1Dws related

Buyue Y; Whinna HC; Sheehan JP. 2008. The heparin-binding exosite of factor IXa is a critical regulator of plasma thrombin generation and venous thrombosis. Blood 112(8):3234-41. [PubMed: 18647957]  [MGI Ref ID J:140143]

Cheng Q; Tucker EI; Pine MS; Sisler I; Matafonov A; Sun MF; White-Adams TC; Smith SA; Hanson SR; McCarty OJ; Renne T; Gruber A; Gailani D. 2010. A role for factor XIIa-mediated factor XI activation in thrombus formation in vivo. Blood 116(19):3981-9. [PubMed: 20634381]  [MGI Ref ID J:166481]

Cheng Q; Zhao Y; Lawson WE; Polosukhin VV; Johnson JE; Blackwell TS; Gailani D. 2005. The effects of intrinsic pathway protease deficiencies on plasminogen-deficient mice. Blood 106(9):3055-7. [PubMed: 15985536]  [MGI Ref ID J:123906]

Gui T; Reheman A; Ni H; Gross PL; Yin F; Monroe D; Monahan PE; Stafford DW. 2009. Abnormal hemostasis in a knock-in mouse carrying a variant of factor IX with impaired binding to collagen type IV. J Thromb Haemost 7(11):1843-51. [PubMed: 19583826]  [MGI Ref ID J:166332]

Hoffman M; Harger A; Lenkowski A; Hedner U; Roberts HR; Monroe DM. 2006. Cutaneous wound healing is impaired in hemophilia B. Blood 108(9):3053-60. [PubMed: 16825491]  [MGI Ref ID J:140458]

Liao G; Nayak S; Regueiro JR; Berger SB; Detre C; Romero X; de Waal Malefyt R; Chatila TA; Herzog RW; Terhorst C. 2010. GITR engagement preferentially enhances proliferation of functionally competent CD4+CD25+FoxP3+ regulatory T cells. Int Immunol 22(4):259-70. [PubMed: 20139172]  [MGI Ref ID J:159115]

Ostergaard H; Bjelke JR; Hansen L; Petersen LC; Pedersen AA; Elm T; Moller F; Hermit MB; Holm PK; Krogh TN; Petersen JM; Ezban M; Sorensen BB; Andersen MD; Agerso H; Ahmadian H; Balling KW; Christiansen ML; Knobe K; Nichols TC; Bjorn SE; Tranholm M. 2011. Prolonged half-life and preserved enzymatic properties of factor IX selectively PEGylated on native N-glycans in the activation peptide. Blood 118(8):2333-41. [PubMed: 21700771]  [MGI Ref ID J:176915]

Pawlinski R; Fernandes A; Kehrle B; Pedersen B; Parry G; Erlich J; Pyo R; Gutstein D; Zhang J; Castellino F; Melis E; Carmeliet P; Baretton G; Luther T; Taubman M; Rosen E; Mackman N. 2002. Tissue factor deficiency causes cardiac fibrosis and left ventricular dysfunction. Proc Natl Acad Sci U S A 99(24):15333-8. [PubMed: 12426405]  [MGI Ref ID J:80537]

Sabatino DE; Armstrong E; Edmonson S; Liu YL; Pleimes M; Schuettrumpf J; Fitzgerald J; Herzog RW; Arruda VR; High KA. 2004. Novel hemophilia B mouse models exhibiting a range of mutations in the Factor IX gene. Blood 104(9):2767-74. [PubMed: 15217833]  [MGI Ref ID J:94243]

Yang C; Feng J; Song W; Wang J; Tsai B; Zhang Y; Scaringe WA; Hill KA; Margaritis P; High KA; Sommer SS. 2007. A mouse model for nonsense mutation bypass therapy shows a dramatic multiday response to geneticin. Proc Natl Acad Sci U S A 104(39):15394-9. [PubMed: 17881586]  [MGI Ref ID J:125302]

Yant SR; Meuse L; Chiu W; Ivics Z; Izsvak Z; Kay MA. 2000. Somatic integration and long-term transgene expression in normal and haemophilic mice using a DNA transposon system. Nat Genet 25(1):35-41. [PubMed: 10802653]  [MGI Ref ID J:119595]

Zhang G; Shi Q; Fahs SA; Kuether EL; Walsh CE; Montgomery RR. 2010. Factor IX ectopically expressed in platelets can be stored in alpha-granules and corrects the phenotype of hemophilia B mice. Blood 116(8):1235-43. [PubMed: 20445020]  [MGI Ref ID J:163505]

Health & husbandry

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Health & Colony Maintenance Information

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200.

Colony Maintenance

Breeding & Husbandry	This strain originated on a B6;129P2 background and has been backcrossed to C57BL/6 mice for 10 generations. Matings of homozygous females and hemizygous males may be used when maintaining a live colony.

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

General Supply Notes

• Genomic DNA is available for this strain from the Mouse DNA Resource.

Control Information

	Control
	000664 C57BL/6J
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

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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.

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