Forty families diagnosed by UK centres to have type 1 VWD were recruited. Following review, six families were re-diagnosed to have type 2 VWD, one to have a platelet storage pool disorder, and one family was determined to be unaffected. Direct DNA sequencing of the promoter region and all exons and intronic boundaries of the VWF gene identified six mutations likely to be causative of VWD in index cases of nine of the 32 (28%) confirmed type 1 VWD families. These included R1205H (3614G > A) VWD Vicenza, P1648fsX45 (4944delT), D141G (422A > G) and three splice site mutations: 3108 + 5G > A, 7437 + 1G > A and 3379 + 1G > A. The Y1584C (4751A > G) polymorphism was present in eight additional families. No significant VWF gene mutation or polymorphism was identified in 15 of the 32 type 1VWD index cases (47%). Haplotype studies were performed using a panel of VWF polymorphisms to investigate the segregation in families of VWD phenotype with the VWF gene. In 13 of the 32 families it was likely that VWD segregated with the VWF gene. In eight families (25%) VWD clearly did not segregate with the VWF gene. We suggest that mutation screening of the VWF gene has limited general utility in genetic diagnostic and family studies in type 1 VWD. If genetic studies are performed, the incomplete penetrance and variable expressivity of type 1 VWD must be taken into account. Unless linkage of VWD phenotype with the VWF gene can be clearly demonstrated, the results of any genetic family studies should be interpreted with caution.
"In addition,compound heterozygosity for type 3 or type 2N mutationsinfluence the severity of the disease. Recent studiesperformed in the European Union, the UK, and Canadahave provided some data on the molecular pathology oftype 1 vWD and established that there is a genotype-phenotypecorrelation [80,81,82]; the vWF gene was analyzed in~300 type 1 vWD patients in the 3 studies, which demonstratedthat both allelic and locus heterogeneity should beconsidered to play a role in the molecular pathogenesis oftype 1 vWD. "
[Show abstract][Hide abstract] ABSTRACT: Quantitative and/or qualitative deficiency of von Willebrand factor (vWF) is associated with the most common inherited bleeding disease von Willebrand disease (vWD). vWD is a complex disease with clinical and genetic heterogeneity. Incomplete penetrance and variable expression due to genetic and environmental factors contribute to its complexity. vWD also has a complex molecular pathogenesis. Some vWF gene mutations are associated with the affected vWF biosynthesis and multimerization, whereas others are associated with increased clearance and functional impairment. Moreover, in addition to a particular mutation, type O blood may result in the more severe phenotype. The present review aimed to provide a summary of the current literature on the molecular genetics of vWD.
Conflict of interest:None declared.
"This problem is further underlined by the fact that a substantial number of individuals with low VWF levels have no clear family history of bleeding symptoms and no detectable mutations in the VWF gene (VWF), although is has been anticipated for a long time that type 1 VWD is caused by VWF mutations. Three large studies in Europe, the United Kingdom and Canada showed that only 65% of the type 1 VWD patients have candidate mutations, meaning that 35% have no apparent VWF mutations , , . Therefore it is likely that genetic variations in genes other than VWF may contribute to the variation in VWF levels and bleeding symptoms, as we present in the current study. "
[Show abstract][Hide abstract] ABSTRACT: In type 1 von Willebrand Disease (VWD) patients, von Willebrand Factor (VWF) levels and bleeding symptoms are highly variable. Recently, the association between genetic variations in STXBP5 and STX2 with VWF levels has been discovered in the general population. We assessed the relationship between genetic variations in STXBP5 and STX2, VWF levels, and bleeding phenotype in type 1 VWD patients.
In 158 patients diagnosed with type 1 VWD according to the current ISTH guidelines, we genotyped three tagging-SNPs in STXBP5 and STX2 and analyzed their relationship with VWF:Ag levels and the severity of the bleeding phenotype, as assessed by the Tosetto bleeding score.
In STX2, rs7978987 was significantly associated with VWF:Ag levels (bèta-coefficient (β) = -0.04 IU/mL per allele, [95%CI -0.07;-0.001], p = 0.04) and VWF:CB activity (β = -0.12 IU/mL per allele, [95%CI -0.17;-0.06], p<0.0001). For rs1039084 in STXBP5 a similar trend with VWF:Ag levels was observed: (β = -0.03 IU/mL per allele [95% CI -0.06;0.003], p = 0.07). In women, homozygous carriers of the minor alleles of both SNPs in STXBP5 had a significantly higher bleeding score than homozygous carriers of the major alleles. (Rs1039084 p = 0.01 and rs9399599 p = 0.02).
Genetic variation in STX2 is associated with VWF:Ag levels in patients diagnosed with type 1 VWD. In addition, genetic variation in STXBP5 is associated with bleeding phenotype in female VWD patients. Our findings may partly explain the variable VWF levels and bleeding phenotype in type 1 VWD patients.
PLoS ONE 07/2012; 7(7):e40624. DOI:10.1371/journal.pone.0040624 · 3.23 Impact Factor
"The highest G allele frequency has been reported in Black North American (0.54) and the lowest in Chinese population (0.06)  . The VWF ISTH database indicates the more frequency of 2385C allele in African compared to Asian population (0.70 in Nigerian vs. 0.04 in Chinese and 0.06 in Japanese population) "
[Show abstract][Hide abstract] ABSTRACT: Defects in von Willebrand factor, a crucial protein in haemostasis, lead to the most common inherited coagulopathy in man, von Willebrand disease. To date, over 350 mutations and 170 single nucleotide polymorphisms of VWF gene have been reported. In the present study, the distribution of two linked VWF gene variants, rs1063856 and rs1063857 have been assessed. The proportional frequency of rs1063856 (2365A/G) and rs1063857 (2385T/C) in healthy individuals were 0.70/0.30. Frequency of polymorphisms was in agreement with predicted geographical distribution. von Willebrand disease was more common in subjects with 2365A and 2385T alleles (odds ratio=1.35), although the difference was not statistically significant (p-values>0.05). The perfect correlation between these two single nucleotide polymorphisms supports their joint contribution in von Willebrand factor biology.
International Journal of Molecular Epidemiology and Genetics 01/2012; 3(1):77-83. · 1.30 Impact Factor
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