Hemophilia B, Factor IX

 

Gene: F9

Transmission: X-linked recessive, variable penetration

For an X-linked recessive genetic disease, a male must have one copy of the mutation in question to be at risk of developing the disease.  All affected males transmit the mutation to all the females of their offspring. A female must have two copies of the mutation in question to be at risk of developing the disease. Females with only one copy of the mutation are not at risk of developing the disease but are carrier animals that can pass the mutation on to future generations.

Mutations: 

Cairn Terrier mutation: Substitution, F9 gene; c.1253 G>A, p.(G418E)

Lhasa Apso mutation: Insertion, deletion, P9 gene; c.548|553 del. ins.T, p.(R183L fs STOP 3)

Labrador Retriever mutation: Deletion of entire F9 gene

Pit Bull Terrier mutation: Deletion from exon1 to exon6 of F9 gene

Airedale Terrier mutation: Insertion, F9 gene; c.1247_1248, ins. 5000 nt

German Wirehaired Pointer mutation: Insertion, F9 gene; insertion truncated LINE-1 sequences

Rhodesian Ridgeback mutation: Substitution, F9 gene; c.731 G>A, p.(G244E)

Hoverwart mutation: Deletion, F9 gene regulatory sequences

Newfoundland mutation: Insertion, F9 gene; c.821_822 ins.A, p.(N274K fs STOP 23)

Medical system: Blood

Breeds: Airedale Terrier, Cairn Terrier, German Wirehaired Pointer, Hovawart, Labrador Retriever, Lhasa Apso, Newfoundland, Rhodesian Ridgeback

Age of onset of symptoms: At birth

Hemophilia B, Factor IX is a genetic disorder in which there is a Factor IX deficiency, a protein essential for platelet clot formation.  Since the gene in question is located on the X chromosome, the disease is related to sex: the males are affected and the females are mainly carriers.  The severity of the clinical signs is variable.  Most dogs are not bothered by this condition other than the fact that mild bleeding takes a little longer to stop than normal. Those that are moderately affected may have spontaneous nose bleeds and bruises. Severely affected animals have not only internal bleeding but also large hematomas under the skin and in the muscles, black blood in the feces and sometimes bleeding in the joints.  These animals are at risk of profuse bleeding after trauma or surgery which can be fatal.

 

References:

OMIA link: [0438-9615]

Donner J, Freyer J, Davison S, et al. (2023) Genetic prevalence and clinical relevance of canine Mendelian disease variants in over one million dogs.  PLoS Genet. 19(2):e1010651. [pubmed/36848397]

Brenig, B., Steingräber, L., Shan, S, et al. (2019) Christmas disease in a Hovawart family resembling human hemophilia B Leyden is caused by a single nucleotide deletion in a highly conserved transcription factor binding site of the F9 gene promoter. Haematologica 104:2307-2313. [pubmed/30846504]

Nichols TC, Hough C, Agersø H, et al. (2016) Canine models of inherited bleeding disorders in the development of coagulation assays, novel protein replacement and gene therapies.  J Thromb Haemost. 14(5):894-905. [pubmed/26924758]

Mischke R, Kühnlein P, Kehl A, et al. (2011) G244E in the canine factor IX gene leads to severe haemophilia B in Rhodesian Ridgebacks. Vet J. 187(1):113-8. [pubmed/20303304]

Sugahara Y, Catalfamo J, Brooks M, et al. (1996) Isolation and characterization of canine factor IX. Thromb Haemost. 75(3):450-455 [pubmed/8701406]

Evans JP, Brinkhous KM, Brayer GD, et al. (1989) Canine hemophilia B resulting from a point mutation with unusual consequences. PNAS USA 86:10095-10099. [pubmed/2481310]