Genetic alteration of the D2 domain abolishes von Willebrand factor multimerization and trafficking into storage. J Thromb Haemost 2009 Apr;7(4):641-50
Date
02/05/2009Pubmed ID
19192112Pubmed Central ID
PMC2745278DOI
10.1111/j.1538-7836.2009.03290.xScopus ID
2-s2.0-63049092852 (requires institutional sign-in at Scopus site) 25 CitationsAbstract
BACKGROUND: The large von Willebrand factor (VWF) propeptide (VWFpp) plays a critical role in the multimerization and regulated storage of the mature VWF protein. Although our laboratory and others have identified mutations in von Willebrand disease patients that disrupt VWF multimerization, little is known about the affect of mutations on the regulated storage of VWF.
PATIENTS/METHODS: We identified a heterozygous 18 base pair, in-frame deletion in exon 12 of the VWF gene in a patient with an unusual, dimer-intense multimer pattern. This deletion results in loss of amino acids 436-442 of VWFpp, which include one cysteine.
RESULTS: Through expression studies, we demonstrate reduced secretion, loss of VWF multimerization, and defective regulated storage of the variant VWF. The loss of VWF storage is secondary to loss of propeptide storage resulting from an apparently defective sorting signal on VWFpp. Suprisingly, coexpressed wild-type VWF or VWFpp functioned in trans to partially restore multimerization of VWF from the variant allele.
CONCLUSIONS: The deletion of six amino acids in VWFpp results in defects in VWF processing, regulated storage, and function. Although VWFpp may usually function in a homotypic fashion, acting on its own mature VWF subunit, VWFpp may retain the ability to function in trans on VWF expressed from the variant allele.
Author List
Haberichter SL, Allmann AM, Jozwiak MA, Montgomery RR, Gill JCAuthor
Robert R. Montgomery MD Emeritus Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
HeterozygoteHumans
Mutation
Protein Multimerization
Protein Sorting Signals
Protein Structure, Tertiary
Protein Transport
Sequence Deletion
von Willebrand Factor
