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The genetics of Canadian type 3 von Willebrand disease: further evidence for co-dominant inheritance of mutant alleles.

AbstractBACKGROUND:
Type 3 von Willebrand disease (VWD) is the most severe form of the disease and is classically inherited in an autosomal recessive fashion.
OBJECTIVES:
The aim of the current study was to investigate the molecular pathogenesis of a Canadian cohort of type 3 VWD patients.
PATIENTS AND METHODS:
Thirty-four families comprised of 100 individuals were investigated. Phenotypic data, including bleeding scores (BS), von Willebrand factor (VWF) laboratory values and anti-VWF inhibitor status were included as well as sequence analysis.
RESULTS:
We identified 31 different mutations (20 novel): 8 frameshift, 5 splice site, 9 nonsense, 1 gene conversion, 6 missense and 2 partial gene deletion mutations. The majority of mutations identified were in the propeptide (42%); index cases (IC) with these mutations exhibited more severe bleeding (BS = 22) than those with mutations elsewhere in VWF (BS = 13). Sixty-two out of 68 (91%) mutant alleles were identified. Twenty-nine IC (85%) had a VWF null genotype identified; 17 homozygous, 12 compound heterozygous. In five IC (15%), two mutant VWF alleles were not identified to explain the type 3 VWD phenotype. In four ICs only one mutant VWF allele was identified and in one IC no mutant VWF alleles were identified.
CONCLUSIONS:
We have investigated the molecular pathogenesis of a Canadian cohort of type 3 VWD patients. Obligate carriers are not phenotypically silent in the Canadian population; 48% have been diagnosed with type 1 VWD. In approximately 50% of families in this study the inheritance pattern for type 3 VWD is co-dominant and not recessive.
AuthorsM Bowman, A Tuttle, C Notley, C Brown, S Tinlin, M Deforest, J Leggo, V S Blanchette, D Lillicrap, P James, Association of Hemophilia Clinic Directors of Canada
JournalJournal of thrombosis and haemostasis : JTH (J Thromb Haemost) Vol. 11 Issue 3 Pg. 512-20 (Mar 2013) ISSN: 1538-7836 [Electronic] England
PMID23311757 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Copyright© 2013 International Society on Thrombosis and Haemostasis.
Chemical References
  • Isoantibodies
  • von Willebrand Factor
Topics
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Blood Coagulation (genetics)
  • Canada (epidemiology)
  • Child
  • Child, Preschool
  • Cohort Studies
  • Female
  • Genes, Dominant
  • Genetic Predisposition to Disease
  • HEK293 Cells
  • Heredity
  • Heterozygote
  • Homozygote
  • Humans
  • Infant
  • Isoantibodies (blood)
  • Male
  • Middle Aged
  • Mutation
  • Phenotype
  • Severity of Illness Index
  • Surveys and Questionnaires
  • Transfection
  • Young Adult
  • von Willebrand Disease, Type 3 (blood, diagnosis, epidemiology, genetics)
  • von Willebrand Factor (genetics, immunology, metabolism)

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