2 Matching Annotations
  1. Nov 2024
    1. 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.

  2. Oct 2024
    1. 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