Von Willebrand disease type 2M "Vicenza" in Italian and German patients: Identification of the first candidate mutation (G3864A; R1205H) in 8 families

Von Willebrand disease type 2M "Vicenza' (VWD 2M V) is characterised by aut osomal dominant inheritance, low von Willebrand factor (VWF) and the presen ce of 'supranormal" multimers in plasma. This specific phenotype has been d escribed in Italian and recently also in German patients. The molecular def ect is linked to the VWF gene. However, no specific mutations have been ide ntified until now. We analysed the complete coding region and adjacent intr on sequences of the VWF gene in Italian families in comparison to German fa milies with VWD 2M V by a PCR-based mutation screening, combined with SSC- and heteroduplex-analysis of exons 2 through 52, followed by direct sequenc ing. We identified the first heterozygous candidate mutation (G3864A; R1205 H) in all affected members of the 7 Italian families and in 1 German patien t but not in the unaffected family members nor on 100 chromosomes of normal subjects, suggesting a causal relationship between the mutation and the ph enotype. Haplotype identity, with minor deviations in one Italian family, s uggests a common but not very recent genetic origin of R1205H.