- Nov 2024
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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Disorder studied: Type 1 von Willebrand disease (T1-VWD).
Type of study: Translational
Model organism: Mouse (inbred strains) Obtained from Jackson Laboratory
Analyses:
VWF plasma protein quantitation (ELISA)
Hertiability calculations
PCR genotyping
QTL analysis
Allele-specific primer extension analysis
Results:
Identified new modifier of VWF known as (Mvwf5). Also found two loci unliked to Vwf known as (Mvwf6-7)
Mice with this variant displayed statistically significant decrease in VWF levels, recapitulating the decreasing patterns displayed in humans.
However, another strain of inbred mice with a different mutation did not show an age-dependent decrease in VWF. Suggests strain-specific differences in regulation of VWF levels over time.
Mvwf5 is a cis-regulatory variant altering Vwf mRNA expression.
This is a natural variant of the Vwf allele among inbred strains of mice. Found this variant causes elevation in steady-state levels of Vwf mRNA.
Authors state findings show equivalent of of type 1 VWD is remarkably common in mice and humans. ALso state the Mvwf1 analysis in wild mouse populations suggest this locus is under selective pressure.
Of the 5 potential modifier loci identified, 3 display conservation of synteny with potential human modifier loci.
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- Oct 2024
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Disease: Von Willebrand Disease (VWD) type 1
Patient(s): 13 yo, female and 14 yo, female, both Italian
Variant: VWF NM_000552.5: c.820A>C p. (Thr274Pro)
Dominant negative effect
Heterozygous carrier
Variant located in the D1 domain on VWF
Phenotypes:
heterozygous carriers have no bleeding history
reduced VWF levels compatible with diagnosis of VWD type 1
increased FVIII:C/VWF:Ag ratio, suggests reduced VWF synthesis/secretion as possible phathophysiological mechanism
Normal VWFpp/VWF:Ag ratio
Modest alteration of multimeric pattern in plasma and platelet multimers
plasma VWF showed slight increase of LMWM and decrease of IMWM and HMWM
Platelet VWF showed quantitative decrease of IMWM, HMWM, and UL multimers
In silico analysis:
SIFT, ALIGN, GVD Polyphen 2.0, SNP&GO, Mutation Taster, Pmut all suggest damaging consequences.
PROVEAN and Effect suggest neutral effect
according to ACMG guidelines this variant was classified as pathogenic
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