Hemophilia A

 

Gene: F8

Transmission: X-linked recessive

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:

Irish Setter mutation: Inversion, F8 gene; inversion of an intron with splicing error and premature termination

German Shepherd type (I) mutation: Substitution, F8 gene; c.98 G>A, p.(W33 STOP), exon1

German Shepherd type (II) mutation: Substitution, F8 gene; c.1700 G>A, p.(C567Y)

Boxer mutation: Substitution, F8 gene; c.1469 C>G, p.(P490R)

Old English Sheepdog mutation : Substitution, F8 gene; c.1786 C>T, p.(R596 STOP)

Rhodesian Ridgeback mutation: Insertion, F8 gene; c.4824_4825 ins. 221 nt SINE sequences

Labrador Retriever mutation: Deletion, F8 gene; c.2923_2924 del, p.(E975K fs STOP 8)

Medical system: Blood

Breeds : Boxer, German Shepherd, Havanese, Irish Setter, Labrador Retriever, Old English Sheepdog, Rhodesian Ridgeback, Schnauzer - Miniature

Hemophilia A is caused by a deficiency in Coagulation Factor VIII, a protein involved in the coagulation reaction within the intrinsic coagulation pathway.  Mutations within the F8 gene are the genetic cause of the disease, and a number of mutations are reported which tend to be breed specific. When the endothelium layer of blood vessels is damaged, for example because of tooth loss, surgery, or trauma, affected dogs form hematomas very easily and experience excessive bleeding of longer than normal duration.  They may also experience spontaneous nasal bleeding.  There’s also a risk of limping if blood accumulates in the joints.  The severity of symptoms can vary between susceptible animals, and male animals are much more prone to having problems than female animals.  Despite these symptoms, the susceptible animal should have a normal life expectancy if it does not suffer severe trauma and fatal bleeding.

Since the F8 gene is located on the X chromosome, hemophilia A is sex-linked.  Typically, male animals are affected by the disease and healthy females are carriers of the mutation.  As carrier mothers are easily identified by their affected male offspring, mutations in the F8 gene that cause hemophilia A tend to be found in isolated pedigrees and be self-limiting.  It should be noted that mutations in other X chromosome genes (F9) and in autosomal genes (vWF) can also be the cause hemophilia, as can environmental factors.

 

References:

OMIA link: [0437-9615]

Brockmann M, Mensing N, von Luckner J, et al. (2023) Hemophilia A in a litter of Border Collies caused by a one base pair deletion in the F8 gene. Vet Clin Pathol 52(4) :607-612.  [pm/38104983]

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]

Hytönen MK, Viitanen S, Hundi S, et al. (2023) A frameshift deletion in F8 associated with hemophilia A in Labrador Retriever dogs. Anim Genet.  [pubmed/37438956]

West N, Butterfield S, Rusbridge C, et al. (2023) Non-traumatic hemorrhagic myelopathy in dogs. J Vet Intern Med37(3) :1129-1138.  [pubmed/37095733]

Kehl A, Haaland A, Langbein-Detsch, I, Mueller E. (2021) A SINE insertion in F8 gene leads to severe form of hemophilia A in a family of Rhodesian Ridgebacks. Genes (Basel) 12(2):134. [pubmed/33494213]

Lozier JN, Kloos MT, Merricks EP, Lemoine N, et al. (2016) Severe Hemophilia A in a Male Old English Sheep Dog with a C→T Transition that Created a Premature Stop Codon in Factor VIII. Comp Med 66:405-411. [pubmed/27780008]

Christopherson PW, Bacek LM, King KB, Boudreaux MK. (2014) Two novel missense mutations associated with hemophilia A in a family of boxers, and a German shepherd dog. Vet Clin Pathol. 43(3):312-6. [pubmed25040606]

Mischke R, Wilhelm Ch, Czwalinna A et al. (2011) Canine haemophilia A caused by a mutation leading to a stop codon.  Veterinary Record 169:496b. [pubmed/21949058]

Hough C, Kamisue S, Cameron C, et al. (2002) Aberrant splicing and premature termination of transcription of the FVIII gene as a cause of severe canine hemophilia A: Similarities with the intron 22 inversion mutation in human hemophilia Thrombosis & Haemostasis 87:659-665.  [pm/12008949]

Lozier JN, Dutra A, Pak E, et al. (2002) The Chapel Hill hemophilia A dog colony exhibits a factor VIII gene inversion Proceedings of the National Academy of Sciences of the United States of America 99:12991-12996.  [pm/12242334]

 

Contributed by: Zoé Bellemare-Alford and Liana Maillette, Faculty of Veterinary Medicine, University of Montreal. (Translation DWS).