Hemophilia A

Gene: F8

Transmission: Chr.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:

Japanese Brown mutation: Substitution, F8 gene; c.6458 T>A, p.(L2153H), chr.X.

Fleckvieh-Simmental mutation: Substitution, F8 gene; c.134 A>T, p.(H45L), chr.X.

Medical systems: Blood

Breeds: Japanese Brown (Akaushi), Fleckvieh-Simmental

Age of onset of symptoms: From birth.

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 two mutations are reported in cattle.  When the endothelium layer of blood vessels is damaged, for example because of trauma or surgery, affected animals form hematomas very easily and experience excessive bleeding of longer than normal duration.  Blood chemistry shows prolonged Activated partial thromboplastin test (APTT) results. 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.  The mutation in the Simental breed tends to result in milder symptoms compared to the mutation associated with the Japanese Brown breed.

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 asymptomatic 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: [0437-9913]

Reinartz S, Weiß C, Mischke R, Distl O. (2018) A mild form of haemophilia A is associated with two factor VIII missense mutations in German Fleckvieh cattle. Anim Genet 49(4):350-351.  [pm/29774585]

Khalaj M, Abbasi A R, Shimojo K, et al. (2009). A missense mutation (p.Leu2153His) of the factor VIII gene causes cattle haemophilia A. Anim Genet 40(5):763‑765. [pm/19456318]

Moritomo Y, Shimojo K, Miyadera K, et al. (2008). Clinical and pathological aspects of hemophilia a in Japanese Brown cattle. J Vet Med Sci 70(3): 293‑296.  [pm/18388431]

Healy PJ, Sewell CA, Exner T, et al. (1984) Haemophilia in Hereford cattle: factor VIII deficiency. Aust Vet J 61:132-3.  [pm/6743161]

Contributed by: Léa Chicoine and Olivier Aïtcin, Class of 2028, Faculty of Veterinary Medicine, University of Montreal.  (Translation, DWS)