Thrombopathia in Landseer

Thrombopathia is an inherited genetic disease that causes increased bleeding. The affected breeds are in particular: Basset, Landseer and American Eskimo dog. In affected dogs, three distinct mutations have been identified that are associated with impaired function of blood platelets and heightened tendency to bleed.

The protein Rap 1 is essential for the blood platelets. A high amount of it is created not only in platelets, but also in neutrophils and in the brain. It plays an important role in several cell processes from platelets or neutrophils activation to cell proliferation and differentiation.  The platelets contain high levels of Rap1b (a variant of Rap1). In platelets, this protein is involved in activation of integrin that is needed for the activation of fibrinogen initiating the platelet aggregation at sites of vascular injury. Rap 1B is essential for the normal function of platelets and the whole process of blood coagulation.  The protein Rap1b is activated by CalDAG-GEFI (Calcium-Diacylglycerol Guanine Nucleotide Exchange Factor I) that is encoded by RASGRP1-gene. Thrombopathia is caused by mutation in this gene that affects the protein RAb1b due to the above mentioned sequence and results in substantial defects of blood clotting process.

In Eskimo dogs, the mutation c.452_453insA RASGRP1was described that causes a shift in the reading frame. In Bassets, the same gene may include deletion of three bases c.509_511delTCT and Landseer dogs may have a substitute point mutation c.982C>T in RASGRP1 gene. The substantial symptoms in affected dogs are nose bleeding, gum bleeding and petechiae.

Thrombopathia is a recessively inherited disease. The disease develops in dogs which inherit the mutated gene from each parent.  These dogs are designated as P/P (positive/positive). The carriers of the mutated gene are designated as N/P (negative/positive). The carriers inherited the mutated gene from one parent only and are without clinical signs. However, they pass the disease on to their offspring.  When mating two heterozygotes (N/P), there will be theoretically 25% of the offspring healthy, 50% of the offspring will be carriers and 25% of the offspring will inherit the mutated gene from both parents and will be affected by Thrombopathia.  Mating one healthy dog (N/N) with a carrier of this mutation (N/P) will theoretically produce 50% carriers and 50% healthy offspring.  If a carrier (N/P) is mated with an affected dog (P/P), there will be theoretically 50% affected dogs and 50% carriers.

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Reference:

Boudreaux, M. K., Catalfamo, J. L., & Klok, M. (2007). Calcium-diacylglycerol guanine nucleotide exchange factor I gene mutations associated with loss of function in canine platelets. Translational Research, 150(2), 81-92.