Presence of a Common Haplotype in the Turkish VWD Patients.

Abstract 4435

Von Willebrand Factor (VWF) is the cruical molecule in the initiation of hemostatic response to vascular injury. Quantitative or qualitative defects in VWF are associated with Type 1/Type 3 or Type 2 von Willebrand disease (VWD), respectively. VWF is encoded by the VWF gene composed of 52 exons and located on chromosome 12. Nonfunctional copy of the VWF gene containing a region from exon 22 to exon 34 is located on chromosome 22. Plasma VWF levels show a five-fold range within a normal population and genetic varaiablity at the VWF locus accounts for 30% of this variance. VWF gene exhibits a high variablity in its sequence. More than 150 polymorphisms and more than 200 different mutations have been reported in VWF database. Most of the polymorphisms and mutations are detecetd in the region that is duplicated in the pseudogene. Genetic recombination between the gene and its pseudogene may account for this high variability in the VWF gene. Highly polymorphic structure of the VWF gene suggests that haplotypic interactions may account for the variable expressivity of the gene. In this study we report presence of a common haplotype structure in exon 28 of the VWF gene in the Turkish VWD patients. Patient population includes Type1, Type 3 and Type 2 VWD patients. DNA sequencing analysis of 32 VWD patients revealed presence of a novel c.4453G>C change in exon 28 of the 23 patients. c.4453G>C change results in the p.1485V>L substitution. Individuals having p.1485V>L substitution was also carrier for the previously identified c.4500G>A (p.1500A), 4503C>T (p.1501F), c.4508T>C (p.1503L>P), and c. 4517C>T (p.1506S>L) changes in exon 28. c.4500G>A, 4503C>T changes were reported as polymorphisms and c.4508T>C and c. 4517C>T changes were reported as mutations identified in VWD Type 2A patients in VWF database. To determine whether these alterations represent a haplotype, we are currently analyzing exon 28 of the parents of the carrier patients. In 8 of the 11 patient families analyzed, patients inherited the haplotype from the parents. These preliminary data suggests presence of a common haplotype for the Turkish VWD patients. Future studies with the rest of the patient families and normal population will determine whether this haplotype is a benign haplotype or associated with VWD.