RGD Reference Report - A novel F8 -/- rat as a translational model of human hemophilia A. - Rat Genome Database

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A novel F8 -/- rat as a translational model of human hemophilia A.

Authors: Nielsen, LN  Wiinberg, B  Hager, M  Holmberg, HL  Hansen, JJ  Roepstorff, K  Tranholm, M 
Citation: Nielsen LN, etal., J Thromb Haemost. 2014 Aug;12(8):1274-82. doi: 10.1111/jth.12635.
RGD ID: 11530071
Pubmed: PMID:24931420   (View Abstract at PubMed)
DOI: DOI:10.1111/jth.12635   (Journal Full-text)

BACKGROUND: In preclinical hemophilia research, an animal model that reflects both the phenotype and the pathology of the disease is needed. OBJECTIVES: Here, we describe the generation and characterization of a novel genetically engineered F8(-/-) rat model. METHODS: The rats were produced on a Sprague Dawley background with the zinc finger nuclease technique. A founder with a 13-bp deletion in exon 16 causing a premature translational stop in the C-terminal part of the A3 domain of factor VIII was selected, and a breeding colony was established. RESULTS: Seventy per cent of the homozygous rats had clinically manifest spontaneous hemorrhagic episodes that needed treatment. The F8(-/-) rats had no detectable FVIII activity, and had a significantly prolonged activated partial thromboplastin time (APTT) and clot formation time as compared with wild-type (WT)/WT rats. In vitro spiking of rat plasma with human recombinant FVIII resulted in dose-dependent normalization of the APTT. CONCLUSION: On the basis of the targeted deletion in F8, and the distinct physical and analytic characteristics of the rat, we conclude that an FVIII-deficient rat strain has been generated that has the potential to contribute greatly to translational research.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
F8Ratfactor VIII deficiency  IMP  RGD 
F8Humanfactor VIII deficiency  ISOF8 (Rattus norvegicus) RGD 
F8Mousefactor VIII deficiency  ISOF8 (Rattus norvegicus) RGD 
F8em1SageRatfactor VIII deficiency  IMP  RGD 
SD-F8em1Sage-/-/NovoRatfactor VIII deficiency MODEL: spontaneousIMP  RGD 
F8RatHemorrhage treatmentISOF8 (Homo sapiens) RGD 
F8HumanHemorrhage treatmentIDA  RGD 
F8MouseHemorrhage treatmentISOF8 (Homo sapiens) RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
F8Ratdecreased circulating serum albumin level  IMP as compared to wild type Sprague DawleyRGD 
F8em1SageRatdecreased circulating serum albumin level  IMP  RGD 
SD-F8em1Sage-/-/NovoRatdecreased circulating serum albumin level  IMP as compared to wild type Sprague DawleyRGD 
F8Ratdecreased circulating total protein level  IMP as compared to wild type Sprague DawleyRGD 
F8em1SageRatdecreased circulating total protein level  IMP  RGD 
SD-F8em1Sage-/-/NovoRatdecreased circulating total protein level  IMP as compared to wild type Sprague DawleyRGD 
F8Rathemorrhage  IMP  RGD 
F8em1SageRathemorrhage  IMP  RGD 
SD-F8em1Sage-/-/NovoRathemorrhage  IMP  RGD 
F8Ratincreased leukocyte cell number  IMP as compared to wild type Sprague DawleyRGD 
F8em1SageRatincreased leukocyte cell number  IMP  RGD 
SD-F8em1Sage-/-/NovoRatincreased leukocyte cell number  IMP as compared to wild type Sprague DawleyRGD 
F8Ratincreased partial thromboplastin time  IMP as compared to wild type Sprague DawleyRGD 
F8em1SageRatincreased partial thromboplastin time  IMP  RGD 
SD-F8em1Sage-/-/NovoRatincreased partial thromboplastin time  IMP as compared to wild type Sprague DawleyRGD 
F8Ratthrombocytosis  IMP as compared to wild type Sprague DawleyRGD 
F8em1SageRatthrombocytosis  IMP  RGD 
SD-F8em1Sage-/-/NovoRatthrombocytosis  IMP as compared to wild type Sprague DawleyRGD 
Objects Annotated

Genes (Rattus norvegicus)
F8  (coagulation factor VIII)
F8em1Sage  (coagulation factor VIII, procoagulant component; zinc finger nuclease induced mutant1, Sage)

Genes (Mus musculus)
F8  (coagulation factor VIII)

Genes (Homo sapiens)
F8  (coagulation factor VIII)

Strains
SD-F8em1Sage-/-/Novo  (NA)

Objects referenced in this article
Strain iNP-Npyem6Sage+/-/Iusm null Rattus norvegicus
Strain SD-F8em1Sage+/-/Novo null Rattus norvegicus
Strain SD-F8em1Sage/Novo null Rattus norvegicus

Additional Information