In other species: pig

Categories: Haematopoietic system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 193400 (trait) , 613160 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal

Disease-related: yes

Key variant known: yes

Year key variant first reported: 1998

Cross-species summary: The von Willebrand factor (vWF) is a large multimeric plasma glycoprotein required for platelet adhesion and aggregation. A deficiency or defective vWF results in von Willebrand disease (vWD). vWD are often classified in 3 different types based on the clinical severity and quantity and multimere size of von Willebrand factor. Type I is characterized by low plasma vWF concentrations and mild to moderate bleeding symptoms. Type II disorder is characterised by qualitative abnormalities of the vWF protein and moderate to severe bleeding. Type III is the most severe form of vWD with no detectable or a severe quantitative deficiency of vWF.

Species-specific name: Disease is also called Type 1 von Willebrand Disease, vWDI, angiohaemophillia, von Willebrand disorder, von Willebrand factor deficiency

Inheritance: Dodds (1984) and Segert et al. (2019) report the mode of inheritance as autosomal dominant with incomplete penetrance in Doberman Pinscher and Kromfohrländer. In other breeds a recessive mode of inheritance has been proposed (Segert et al. 2019).

Molecular basis: As reported by Boudreaux (2012), a likely causal mutation for this disorder in Doberman Pinchers was reported in US Patent 6074832, submitted by Brewer et al. (Michigan State University) in 2000. According to the patent, the actual mutation is a synonymous base substitution at nucleotide 7437 in exon 43 (Ser 2479) of the VWF gene, which decreases the effectiveness of a splice site. Gentilini and Turba (2013) provided details of the mutation: it is "a G → A transversion of the last nucleotide of von Willebrand factor (vWf) exon 43 (c.7437G > A, NM_001002932.1) . . . [which] activates a cryptic splice site a few nucleotides upstream of the normal splice site, leading to a frame shift that results in the formation of a truncated protein of 119 amino acids". Donner et al. (2016) reported the presence and/or carrier frequency of the c.7437A variant in the following breeds: Doberman, Manchester Terrier, Bernese Mountain Dog, Barbet, Brazilian Terrier, Coton de Tulear, Kromfohrländer, Dutch Shepherd dog - longhaired. Crespi et al. (2018) reported that the c.7437A variant is only partially associated with the disorder in the Doberman Pinscher breed in Argentina: only 40% of homozygotes and 22% of heterozygotes for the variant showed clinical signs. Segert et al. (2019) reported similar results for the Kromfohrländer breed: only 46% of homozygotes and 23% of heterozygotes for the c.7437A variant showed clinical signs. Segert et al. (2019) also reported that the variant locus shows a significant effect on vWF concentration: "VWF serum concentrations varied from 28 to 137% in wild-type dogs while in heterozygous and homozygous dogs the concentration ranged from 3 to 77% and 1 to 23%, respectively (p < 0.05)".

Clinical features: Type I von Willebrand disease involves a quantitative partial deficiency of von Willebrand factor, which is a protein involved in blood clotting (Boudreaux, 2012). Clinical features can be characterised as increased bleeding tendency. However, this can be variable. Excessive prolonged bleeding from minor wounds, tooth eruptions, heat or surgical incision are observed in clinically affected dogs with low vWF (Barr & McMichael, 2012; Dodds, 1984). Sudden gingival bleeding, epistaxis, gastrointestinal bleeding, haematuria, subcutaneous haematomas, petechiae can also occur (Thomas, 1996). VWD poses a significant risk in surgery or trauma, where clotting function is very important (Thomas, 1996). Treatment of affected dogs is possible (Thomas, 1996). [IT thanks DVM students MacKenzie Anderson and Jesse Wong, who provided the basis of this contribution in April 2022]

Pathology: Platelet count, prothrombin and partial thromboplastin times are usually normal in dogs with vWDI (Burgess et al., 2009). Buccal mucosal bleeding time (BMBT) can be used to determine haemostatic ability. A positive BMBT can indicate vWDI but requires further coagulative tests as it can be present with other coagulopathies. BMBT can also be normal in mild cases (Thomas, 1996). A decreased level of vWF is detected in a vWF:Ag assay with abnormal values of <50% and values of <35% at notable risk of bleeding. vWD dogs will have normal to slightly elevated vWF antigen to collagen binding activity ratios (Burgess et al., 2009). [IT thanks DVM student Jesse Wong, who provided the basis of this contribution in April 2022]

Control: Use of DNA diagnostics as a sole diagnostic tool for vWDI is not advised as the c.7437A variant has been reported to be only partially associated with the disorder in the Doberman Pinscher breed and the Kromfohrländer breed (incomplete penetrance). Quantification of plasma vWF and in vivo and in vitro tests of vWF-dependent platelet function should be used to diagnose the disease and results from such tests may inform future breeding decissions. This may include von Willebrand factor (vWF) antigen (Ag) test, vwF collagen binding assay, buccal mucosal bleeding time (BMBT), complete blood count (CBC), prothrombin (PT) and partial thromboplastin times (PTT), platelet function analysis (PFA-100) (Thomas, 1996; Burgess et al., 2009) [IT thanks DVM student Jesse Wong, who provided the basis of this contribution in April 2022]

Breeds: Doberman Pinscher (Dog) (VBO_0200442), German Shepherd Dog (Dog) (VBO_0200577), Golden Retriever (Dog) (VBO_0200610), Kromfohrlander (Dog) (VBO_0200786), Pembroke Welsh Corgi (Dog) (VBO_0200995), Poodle, Miniature (Dog) (VBO_0201051), Shetland Sheepdog (Dog) (VBO_0201217), Yorkshire Terrier (Dog) (VBO_0201448).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: