The homozygous variant genotype seen in affected dogs did not occur in 98 control Cocker Spaniels. PCR-based genotyping confirmed recessive inheritance. The variant results in a frameshift and premature stop codon which is predicted to truncate almost two-thirds of the encoded protein. The deletion spanned 2460 bp, and included a significant part of the single coding exon of the canine GP9 gene on dog chromosome 20. Variants in human GP9 are associated with Bernard-Soulier syndrome, type C. The GP9 gene encodes a subunit of a platelet surface membrane glycoprotein complex this functions as a receptor for von Willebrand factor, which initiates the maintenance of hemostasis after injury. Whole genome sequencing of one affected dog and visual inspection of the candidate genes identified a deletion in the glycoprotein IX platelet (GP9) gene. Furthermore, the lack of functional GPIb-IX-V was demonstrated by immunocytochemistry.
The affected dogs showed a platelet adhesion defect characterized by macrothrombocytopenia with variable platelet counts resembling human Bernard-Soulier syndrome (BSS).
Four cases of a mild to severe bleeding disorder in Cocker Spaniel dogs are herein presented. However, the causative genetic variant in many dog breeds has until now remained unknown. Breed-specific disease associated genetic variants in only eight different genes are known to cause intrinsic platelet disorders in dogs. Genetically characterized canine forms of platelet disorders provide valuable large animal models for understanding similar platelet disorders in people. Inherited bleeding disorders including abnormalities of platelet number and function rarely occur in a variety of dog breeds, but are probably underdiagnosed.