Molecular basis of von Willebrand disease type IIB: Candidate mutations cluster in one disulfide loop between proposed platelet glycoprotein Ib binding sequences

Anna M. Randi, Ian Rabinowitz, David J. Mancuso, Pier M. Mannucci, J. Evan Sadler

Research output: Contribution to journalArticle

Abstract

Many variants of von Willebrand disease (vWD) with qualitatively abnormal von Willebrand factor (vWF) are recognized. In vWD type IIB, the abnormal protein displays enhanced affinity for a platelet vWF receptor, the glycoprotein Ib-IX complex. 14 patients from 7 unrelated families with vWD type IIB were studied to determine the molecular basis for this phenotype. Specific oligonucleotide primers were used to amplify portions of vWF exon 28 encoding a domain that interacts with the platelet glycoprotein Ib-IX complex. Candidate missense mutations were identified for all 14 patients by DNA sequencing, allele specific oligonucleotide hybridization, and restriction endonuclease digestion. These sequence changes occur in an 11 amino acid segment within a single disulfide loop bounded by Cys(509) and Cys(695). All of these sequence changes are C → T transitions within CG dinucleotides. Six patients from two unrelated families were heterozygous for the encoded sequence Arg(543) → Trp. Seven patients from four unrelated families were heterozygous for the encoded sequence Arg(545) → Cys; this sequence change appears to have occurred independently three times, once as a new spontaneous mutation. One patient with apparently sporadic vWD type IIB was heterozygous for the encoded sequence Val(553) → Met, and this appears to be a new mutation. None of these sequence changes was found in 100 normal alleles. These findings suggest that vWD type IIB may be caused by relatively few distinct mutations, that these mutations may cluster within a specific region of one disulfide loop in vWF domain A1, and that this region can modulate the affinity of vWF for the platelet glycoprotein Ib-IX complex.

Original languageEnglish
Pages (from-to)1220-1226
Number of pages7
JournalJournal of Clinical Investigation
Volume87
Issue number4
Publication statusPublished - Apr 1991

Fingerprint

Type 2 von Willebrand Disease
Platelet Glycoprotein GPIb-IX Complex
Platelet Membrane Glycoproteins
Disulfides
von Willebrand Factor
Mutation
Alleles
von Willebrand Diseases
DNA Primers
DNA Restriction Enzymes
Missense Mutation
DNA Sequence Analysis
Oligonucleotides
Digestion
Exons
Blood Platelets
Phenotype
Amino Acids
Proteins

Keywords

  • Nucleotide transitions
  • Platelet GPIb-IX complex
  • Polymerase chain reaction
  • Structure-function relationships
  • Von Willebrand factor

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Molecular basis of von Willebrand disease type IIB : Candidate mutations cluster in one disulfide loop between proposed platelet glycoprotein Ib binding sequences. / Randi, Anna M.; Rabinowitz, Ian; Mancuso, David J.; Mannucci, Pier M.; Sadler, J. Evan.

In: Journal of Clinical Investigation, Vol. 87, No. 4, 04.1991, p. 1220-1226.

Research output: Contribution to journalArticle

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