The mutational spectrum of type 1 von Willebrand disease: Results from a Canadian cohort study.

@article{James2007TheMS,
  title={The mutational spectrum of type 1 von Willebrand disease: Results from a Canadian cohort study.},
  author={Paula D James and Colleen R P Notley and Carol A. Hegadorn and Jayne Leggo and Angie Tuttle and Shawn Tinlin and Christine E. Brown and Chandler Andrews and Andrea Labelle and Yvette Chirinian and Lee A. O'Brien and Maha Othman and Georges E Rivard and Dilys Rapson and Christine Hough and David Lillicrap},
  journal={Blood},
  year={2007},
  volume={109 1},
  pages={
          145-54
        }
}
In order to evaluate the changes within the VWF gene that might contribute to the pathogenesis of type 1 von Willebrand disease (VWD), a large multicenter Canadian study was undertaken. We present data from the sequence analysis of the VWF gene in 123 type 1 VWD index cases and their families. We have identified putative mutations within the VWF gene in 63% (n = 78) of index cases, leaving 37% (n = 45) with no identified changes. These changes comprise 50 different putative mutations: 31 (62… 

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References

SHOWING 1-10 OF 31 REFERENCES
Founder von Willebrand factor haplotype associated with type 1 von Willebrand disease.
TLDR
It is demonstrated that all the families with the Tyr1584Cys mutation share a common, evolved VWF haplotype, suggesting that this mutation is ancient.
Dominant type 1 von Willebrand disease caused by mutated cysteine residues in the D3 domain of von Willebrand factor.
TLDR
It is concluded that the loss of cysteine pairing in the D3 domain, leaving one free Cysteine, can induce a purely quantitative deficiency of vWF by dominantly suppressing the secretion of normal vWF.
Genetic linkage and association analysis in type 1 von Willebrand disease: results from the Canadian Type 1 VWD Study
TLDR
These studies provide further evidence to support the role for genetic loci other than VWF and ABO in the pathogenesis of type 1 VWD.
Autosomal dominant type 1 von Willebrand disease due to G3639T mutation (C1130F) in exon 26 of von Willebrand factor gene: description of five Italian families and evidence for a founder effect
Twenty‐four apparently unrelated Italian patients with autosomal dominant type 1 von Willebrand disease (VWD) and a clear autosomal pattern of inheritance of bleeding symptoms were screened for the
Two novel mutations, Q1053H and C1060R, located in the D3 domain of von Willebrand factor, are responsible for decreased FVIII‐binding capacity
TLDR
Using site‐directed mutagenesis and transient expression in COS‐7 cells, it was showed that both mutations, although located in the D3 domain of VWF, outside the tryptic fragment containing the FVIII domain, dramatically decrease the binding ofVWF to FV III.
Genetics of classic von Willebrand's disease. I. Phenotypic variation within families.
In order to determine the phenotypic vanability within families transmitting classic von Willebrand’s disease (vWd). a single cross-sectional examination was made of two large seven-generation vWd
Von Willebrand disease type 1: a diagnosis in search of a disease.
TLDR
Many patients diagnosed with VWD type 1 do not have a specific hemorrhagic disease at all, which limits the utility of the diagnosis, and an empirical epidemiologic approach like that applied to other modest risk factors for disease such as elevated cholesterol and high blood pressure should be substituted.
A novel modifier gene for plasma von Willebrand factor level maps to distal mouse chromosome 11.
TLDR
It is demonstrated that a single dominant gene accounts for the low VWF phenotype of RIIIS/J mice in crosses with several other strains, suggesting a gain-of-function mutation in a unique component of VWF biosynthesis or processing.
Serial studies in von Willebrand's disease: variability versus "variants".
TLDR
The variability of laboratory findings in von Willebrand's disease (vWd) was evaluated by performing serial studies of bleeding time, factor VIII coagulant activity, factor-VIII-related antigen and ristocetin cofactor, and a classification of "variants" of vWd based solely on such studies may be inappropriate.
...
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