Abstract
Hemophilia A is the most common coagulation factor disorder in humans and dogs. The disease is characterized by the lack or diminished activity of Factor VIII (FVIII), caused by variants in the F8 gene and inherited as an X chromosomal trait. Two related male Rhodesian Ridgebacks were diagnosed with Hemophilia A due to reduced FVIII activity. The purpose of the study was to determine the genetic cause and give breeding advice for the remaining family members in order to eradicate the variant. By Sanger sequencing a short interspersed nuclear element (SINE) insertion in exon 14 of the F8 gene was found. Perfect correlation of this genetic variant with clinical signs of hemophilia A in the family tree, and the lack of this genetic variant in more than 500 unrelated dogs of the same and other breeds, confirms the hypothesis of this SINE being the underlying genetic cause of Hemophilia A in this family. The identification of clinically unaffected female carriers allows subsequent exclusion of these animals from breeding, to avoid future production of clinically affected male offspring and more subclinical female carriers.
Highlights
Inherited bleeding disorders encompass aberrations in primary hemostasis, coagulation, and fibrinolysis caused by genetic variants interfering directly or indirectly with platelet function
Hemophilia A is the most common coagulation factor disorder in dogs resulting from mutations in F8 gene [1,2]
We identified a structural variant in exon 14 of the F8 gene as a probable genetic cause of hemophilia A in a family of Rhodesian Ridgebacks
Summary
Inherited bleeding disorders encompass aberrations in primary hemostasis, coagulation, and fibrinolysis caused by genetic variants interfering directly or indirectly with platelet function. Hemophilia A is the most common coagulation factor disorder in dogs resulting from mutations in F8 gene [1,2]. Factor VIII (FVIII), one of the largest coagulation factors, consists of a heavy and a light chain. It is present in the blood linked to von Willebrand factor (vWF) in a non-covalent complex. In its activated form, FVIIIa acts as a cofactor for the prothrombinase complex in the intrinsic coagulation pathway by catalyzing activation of FX in the presence of FIXa [3]. As the F8 gene lies on the X chromosome, hemophilia A is inherited in an X chromosomal recessive manner. Male dogs are phenotypically affected with just one mutated X chromosome (named hemizygotes) while female dogs are heterozygous carriers passing the mutated allele to its offspring
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