A common frameshift mutation in von Willebrand factor does not alter mRNA stability but interferes with normal...

Area of Science:

• Genetics
• Hematology
• Molecular Biology

Background:

• Quantitative von Willebrand factor (VWF) defects cause type 1 and 3 von Willebrand disease (VWD).
• A specific VWF exon 18 deletion mutation is linked to VWD.
• The prevalence of this mutation varies geographically.

Purpose of the Study:

• Characterize the VWF expression defect caused by the VWF exon 18 deletion.
• Investigate the mutation's effect on VWF protein processing, folding, and function.
• Determine the mutation's prevalence in US VWD patients.

Main Methods:

• Genetic analysis of VWD patients.
• Recombinant VWF expression and transfection studies.
• VWF protein analysis (retention, processing, propeptide levels).

Main Results:

• The exon 18 deletion mutation causes a frameshift, leading to premature VWF translation termination.
• Mutant VWF mRNA is stable, but the truncated protein is retained intracellularly without propeptide processing, indicating misfolding.
• Homozygous individuals have severely reduced plasma VWF propeptide; heterozygotes show moderate reduction.
• The mutant VWF does not exhibit a dominant-negative effect on wild-type VWF.
• The mutation is infrequent among US type 3 VWD patients.

Conclusions:

• The VWF exon 18 deletion mutation causes type 1 and 3 VWD through intracellular retention and misfolding of truncated VWF.
• Unlike type 2A VWD, this mutation does not impair normal VWF function via a dominant-negative mechanism.
• Geographic variation in mutation frequency exists, with lower prevalence in the US compared to Sweden and Germany.