Impact of 789Ala/Ala genotype on quantitative type of von Willebrand disease

Abstract

von Willebrand factor (VWF) is a complex multimeric plasma glycoprotein encoded by an approximately 178-kb large VWF gene located on the short arm of chromosome 12 (12p13.2). VWF plays an important role in hemostasis through binding with platelet GpIbalpha receptors. We made an attempt to correlate the 789Ala/Ala genotype of the VWF with VWF:Ag level in different types of unrelated von Willebrand disease (VWD) patients and healthy controls. VWF assays and other coagulation screening tests have been done for all 103 (50 male, 53 female) different types of index VWD patients including 19 type 1, 55 type 2, and 29 type 3 VWD patients. Genotypes were detected by polymerase chain reactions followed by restriction fragment length polymorphism. The genotype 789Ala/Ala was found in 26.3% type 1 and in 31.0% type 3 patients. This genotype was not found in any of type 2 patient or healthy controls. Overall, 789Ala/Ala genotype was found significantly higher (P < 0.001) in quantitative type (type 1 and type 3) VWD that is occurred due to low VWF:Ag level. These results demonstrate that mutant homozygous 789Ala/Ala genotype of this polymorphism probably have their functional implications for low plasma VWF:Ag level in quantitative type of VWD.

Unraveling the Influence of Common von Willebrand factor variants on von Willebrand Disease Phenotype: An Exploratory Study on the Molecular and Clinical Profile of von Willebrand Disease in Spain Cohort

“…10 In the present study, the p.Thr789Ala variant was significantly associated with higher plasma VWF:Ag levels, and although there is some controversy regarding the direction of this effect, most previous results agree with these findings. 7,9,[35][36][37][38][39][40] The p.Thr789Ala variant is located in exon 18 of VWF, within the D' domain, which is critically involved in VWF multimerization and secretion, and in the VWF/FVIII interaction. 9,41,42 Although p.Thr789Ala was not predicted to be deleterious by any of the in silico algorithms used (►Table 2), recently, it has been described by in vitro and in vivo assays the mechanism by which this variant would modulate VWF:Ag levels in healthy subjects.…”

Germline de novo mutations and linkage markers vs. DNA sequencing for carrier detection in von Willebrand disease

“…All eight VWD3 families were included for linkage marker including VWF1, VWF2 and Rsa I analysis by PCR as previously described . Restriction digestion other using Rsa I enzyme was done and digested product was analysed on agarose gel . PAGE followed by silver staining was performed to detect the VWF1 and VWF2 alleles.…”

“…Several studies have previously used restriction fragment length polymorphisms and variable number of tandem repeats (VNTR) within intron 40 of the von Willebrand factor (VWF) for tracking the defective alleles in VWD family [4][5][6][7][8][9]. One of these polymorphic sites in VWF exon 18 RsaI (789Thr/Ala), reported to be studied in different populations [7,10]. Studies have reported that VNTR instability is rare and occurs due to gain or loss of ATCT repeat unit [11,12].…”

Coinheritance of Severe von Willebrand Disease With Glanzmann Thrombasthenia

“…Platelet aggregation has been done using platelet-rich plasma (PRP) at a standard count of 300 Â 10 9 /L. 6 Mixing aggregation study of patient PRP with normal pool plasma (NPP) was also performed to confirm the diagnosis of VWD, and response was recorded with the use of aggregometer (Chrono-Log, Havertown, Pennsylvania). The factor VIII coagulant (FVIII:C) activity was assayed by manual clotting method using FVIIIdeficient plasma (Diagnostica Stago, Chausson, Asnieres, France) that has been standardized for the routine purpose in our laboratory.…”