RGD Reference Report - Variable content of von Willebrand factor mutant monomer drives the phenotypic variability in a family with von Willebrand disease. - Rat Genome Database

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Variable content of von Willebrand factor mutant monomer drives the phenotypic variability in a family with von Willebrand disease.

Authors: Chen, J  Hinckley, JD  Haberichter, S  Jacobi, P  Montgomery, R  Flood, VH  Wong, R  Interlandi, G  Chung, DW  Lopez, JA  Di Paola, J 
Citation: Chen J, etal., Blood. 2015 Jul 9;126(2):262-9. doi: 10.1182/blood-2014-11-613935. Epub 2015 May 27.
RGD ID: 11079200
Pubmed: PMID:26019279   (View Abstract at PubMed)
PMCID: PMC4497966   (View Article at PubMed Central)
DOI: DOI:10.1182/blood-2014-11-613935   (Journal Full-text)

Von Willebrand disease (VWD) is an inherited bleeding disorder characterized by incomplete penetrance and variable expressivity. We evaluated a 24-member pedigree with VWD type 2 caused by a T>G mutation at position 3911 that predicts a methionine to arginine (M1304R) change in the platelet-binding A1 domain of von Willebrand factor (VWF). This mutation manifests as an autosomal-dominant trait, with clinical and biochemical phenotypic variability among affected individuals, including differences in bleeding tendency and VWF quantity, activity, and multimer pattern. Sequencing of all VWF coding regions in 3 affected individuals did not identify additional mutations. When expressed in heterologous cells, M1304R was secreted in lower quantities, failed to drive formation of storage granules, and was defective in multimerization and platelet binding. When cotransfected in equal quantities with the wild-type complementary DNA, the mutant complementary DNA depressed VWF secretion, although multimerization was only mildly affected. A llama nanobody (AU/VWFa-11) that detects the mutant A1 domain demonstrated highly variable binding to VWF from different affected members, indicating that the VWF contained different percentages of mutant monomers in different individuals. Thus, the observed variability in VWD phenotypes could in part be determined by the extent of mutant monomer incorporation in the final multimer structure of plasma VWF.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
VWFHumanvon Willebrand's disease 2  IAGP DNA:missense mutation:cds:p.M1304R(human)RGD 
VwfRatvon Willebrand's disease 2  ISOVWF (Homo sapiens)DNA:missense mutation:cds:p.M1304R(human)RGD 
VwfMousevon Willebrand's disease 2  ISOVWF (Homo sapiens)DNA:missense mutation:cds:p.M1304R(human)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Vwf  (von Willebrand factor)

Genes (Mus musculus)
Vwf  (Von Willebrand factor)

Genes (Homo sapiens)
VWF  (von Willebrand factor)


Additional Information