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Thrombopathia Newfoundland Type (TBP)
| Acronym: | TBP |
| Gene: | RASGRP2 |
| Mutation: | c.982C>T |
| Inheritance: | Autosomal recessive |
| Sample type: | CHS (Cheek Swab), WBE (Whole Blood EDTA) |
Genetics and characteristics
Thrombopathia Newfoundland type is an inherited blood clotting disorder affecting the Newfoundland dog breed. The disorder is characterized by blood clotting malfunction, and as such causes increased bleeding. Until now, thrombopathia has been reported among three dog breeds: Basset, Newfoundland, and American Eskimo dog, and they differ from each other by three distinct causative disorders. Platelets are also known as thrombocytes, and they have a key role in bleeding prevention through the clumping of blood vessel injuries. At a site of vascular injury, platelets are exposed to the surface which is not from a blood vessel, and they initiate to aggregate with each other, which results in the formation of a hemostatic plug that will seal the defect. A key role in platelet aggregation has the platelet integrin alphaIIb-beta3, also known as the platelet glycoprotein complex IIb-IIIa. This platelet integrin has a high affinity for fibrin, which in the formation of the blood clot has a role as its stabilizer. In inactivated platelets, the integrin is in its form that has a low affinity for the fibrin, disabling the formation of the blood clot. Agents that can induce affinity of the integrin for fibrinogen are ADP, collagen, thromboxane, and thrombin. Unfortunately, in the case of thrombopathia, these agents do not have an effect on improved platelet aggregation.
Thrombopathia Newfoundland Type is an inherent platelet defects type hemorrhagia. Another type of hemorrhagia or excessive bleeding is extrinsic type, caused due to external factors. The platelets of the affected dog are defective and are unable to form blood clots. The defect in the platelets of the Landseer dogs is suspected to be related to a structural or functional deficiency glycoprotein complex IIb-IIIa, similar to what has been reported in humans with Glanzmann disease and Bernard-Soulier syndrome, human bleeding disorders. Symptoms of canine thrombopathia are spontaneous bleeding. Bleeding occurs as nose bleeding, also known as epistaxis, and from other mucosal surfaces, such as the mouth, gums, etc. Excessive bleeding inside the mouth may be especially present during the change of puppy teeth with permanent teeth. Platelet number, von Willebrand factor, clot retraction, and coagulation are normal, whereas bleeding time is prolonged.
Thrombopathia Newfoundland type is caused by a point mutation in the RASGRP1 gene that causes a shift in the reading frame responsible for the expression of the Rap 1 protein. This shift in the reading frame causes a truncated protein. In a healthy dog, Rap 1 protein is highly expressed in platelets, but also in neutrophils and in the brain. In the platelets variant of Rap 1, protein Rap1b is present at high levels and it has a role in integrin activation. In case of mutation in the RASGRP1 gene, defected protein will not be able to induce integrin activation, which causes improper platelet aggregation and blood clotting. The disorder is inherited in an autosomal recessive manner. Healthy parents of an affected puppy are obligate heterozygotes and therefore carry one mutant allele. Heterozygotes have no symptoms. Dogs homozygous for the mutation will display the symptoms of the Thrombopathia Landseer type. At conception, each cub has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Results Reported As
Test Result |
Interpretation of test result |
CLEAR |
Tested mutation was not detected in animal with „clear“ result. Animal tested as clear has wild-type allele in homozygous state (i.e. two pairs of healthy alleles). It will not develop disease caused by tested mutation.* It will pass only wild-type allele to its offspring. |
CARRIER |
Tested mutation was detected in animal with „carrier“ result. Animal tested as carrier has one wild-type and one mutation allele, it is in heterozygous state. It will not develop disease caused by tested mutation.* It can pass wild-type or mutation allele to its offspring. |
AFFECTED |
Tested mutation was detected in animal with „affected“ result. Animal tested as affected has two copies of mutation alleles affecting the gene. It is likely the animal will experience a genetic disorder due to this mutation.** It will pass only mutation allele to its offspring. |
*Test excludes only tested mutation but not possible unknown mutations or factors that can lead to similar condition/symptoms.
** Potential unknown mutations or multiple other factors can possibly affect the likelihood of experiencing a genetic disorder.
References:
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.