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Defects in type IIA von Willebrand disease: a cysteine 509 to arginine substitution in the mature von Willebrand factor disrupts a disulphide loop involved in the interaction with platelet glycoprotein Ib‐IX
Author(s) -
Lavergne J.M.,
DePaillette L.,
Bahnak B. R.,
Ribba A.S.,
Fressinaud E.,
And D. Meyer,
Pietu G.
Publication year - 1992
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.1992.tb04595.x
Subject(s) - von willebrand disease , von willebrand factor , microbiology and biotechnology , exon , chemistry , arginine , missense mutation , point mutation , platelet membrane glycoprotein , ristocetin , amino acid , cysteine , glycoprotein , gene , biochemistry , biology , mutation , genetics , platelet , enzyme , immunology
Summary Type IIA von Willebrand disease (vWD) is characterized by the loss of high and intermediate weight multimers of von Willebrand factor (vWF) from plasma. The 3’end of exon 28 in the vWF gene from four type IIA vWD patients was amplified by the polymerase chain reaction, cloned and sequenced. Sequencing identified two potential missense mutations resulting in the amino acid substitutions Arg 834Gln and Glu 875Lys in the mature vWF subunit within an area of vWF where mutations in type IIA vWD have been reported. Neither of these amino acid substitutions was found in over 100 normal alleles tested by allele specific oligonucleotide hybridization. A polymorphism (Val 802Leu) was identified in another patient. Other areas of exon 28 were analysed by denaturing gradient gel electro‐phoresis (DGGE) and DNA from one patient demonstrated an irregular DGGE pattern on the 5’end of the exon. Sequencing demonstrated an amino acid substitution of an arginine for cysteine at position 509 adjacent to an area of vWF where defects associated with type IIB vWD have been found. This substitution was not found in 100 normal chromosomes tested by restriction enzyme digestion. The Cys 509Arg substitution eliminates an intramolecular disulphide bridge formed by Cys 509 and Cys 695 which is important to maintain the configuration of vWF functional domains that interact with platelet glycoprotein Ib‐IX.