Characterization of Three Mutations Causing von Willebrand Disease Type IIA in Five Unrelated Families

Aida Inbal; Uri Seligsohn; Nurit Kornbrot; Benjamin Brenner; Paul Harrison; Anna Randi; Ian Rabinowitz; J Evan Sadler

doi:10.1055/s-0038-1648511

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1992; 67(06): 618-622
DOI: 10.1055/s-0038-1648511

Original Articles

Schattauer GmbH Stuttgart

Characterization of Three Mutations Causing von Willebrand Disease Type IIA in Five Unrelated Families

Aida Inbal

¹The Hematology Unit, Beilinson Medical Center, St.Thomas’Hospital, London, U. K.

³Sackler School of Medicine, Israel, St.Thomas’Hospital, London, U. K.

,

Uri Seligsohn

²Institute of Hematology, Tel Aviv Medical Center, Ichilov Hospital, St.Thomas’Hospital, London, U. K.

³Sackler School of Medicine, Israel, St.Thomas’Hospital, London, U. K.

,

Nurit Kornbrot

¹The Hematology Unit, Beilinson Medical Center, St.Thomas’Hospital, London, U. K.

³Sackler School of Medicine, Israel, St.Thomas’Hospital, London, U. K.

,

Benjamin Brenner

⁴Rambam Medical Center, Israel, St.Thomas’Hospital, London, U. K.

,

Paul Harrison

⁵Coagulation Research Unit, The Rayne Institute, St.Thomas’ Hospital, London, U. K.

,

Anna Randi

⁷Department of Medicine and of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, U.S.A.

,

Ian Rabinowitz

⁶Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO, U. S. A.

⁷Department of Medicine and of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, U.S.A.

,

J Evan Sadler

⁶Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO, U. S. A.

⁷Department of Medicine and of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, U.S.A.

› Author Affiliations

Abstract

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Summary

Von Willebrand disease (vWD) type IIA is characterized by decreased ristocetin-induced platelet aggregation, and by the absence from plasma of high molecular weight multimers of von Willebrand factor (vWF). Most mutations causing vWD type IIA are clustered within the A2 domain of the mature vWF subunit that is encoded by exon 28. Using the polymerase chain reaction (PCR), the entire exon 28 from patients with vWD type IIA and normal controls was amplified and sequenced. Three missense mutations were detected that result in the amino acid substitutions Arg(834)→Trp, Gly(742)→Glu, and Ser(743)→Leu. The first mutation occurred independently in three unrelated families; each of the latter mutations was found in one family. By restriction endonuclease analysis and allele-specific oligonucleotide (ASO) hybridization the mutations were confirmed in affected family members and excluded in unaffected members and 50 normal controls. The apparently high frequency of identical independent mutations among patients with vWD type IIA suggests that a precise diagnosis may be possible in a majority of patients using relatively simple recombinant DNA screening assays.

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References

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