Switch to
| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
7
|
| pubmed:dateCreated |
1996-11-7
|
| pubmed:abstractText |
No defects have been reported in moderately severe type 1 von Willebrand disease (vWD) with a clear autosomal dominant inheritance pattern, and the mechanism underlying this form of vWD remains obscure. We have studied a type 1 vWD family with such a dominant phenotype. The entire coding sequence of the von Willebrand factor (vWF) gene was analyzed by direct sequencing of DNA fragments amplified by polymerase chain reaction. Only one candidate mutation T(3445)-->C in exon 26 was detected that predicts a replacement of cysteine (C) at position 386 of the mature vWF subunit by arginine (R). Both mutant and normal vWF alleles were expressed as shown by analysis of platelet mRNA. This substitution segregates with vWD in the family and was not found in 100 unrelated individuals. The recombinant mutant vWF(C386R) was characterized by expression in 293T cells. The secretion of vWF(C386R) was greatly impaired due to retention in the endoplasmic reticulum. In cotransfections of normal and mutant vWF constructs, the vWF(C386R) subunits caused a dose-dependent decrease in the secretion of vWF. The multimer pattern remained nearly normal and consistent with a dominant vWD type 1 phenotype. The importance of the cysteine residues in the D3 domain of vWF in the pathogenesis of dominant type 1 vWD was further shown by the detection of another cysteine mutation, Cys367-->Phe, in two additional unrelated patients with a similar dominant type 1 vWD phenotype. We conclude that the loss of cysteine pairing in the D3 domain, leaving one free cysteine, can induce a purely quantitative deficiency of vWF by dominantly suppressing the secretion of normal vWF.
|
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
AIM
|
| pubmed:chemical | |
| pubmed:status |
MEDLINE
|
| pubmed:month |
Oct
|
| pubmed:issn |
0006-4971
|
| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:day |
1
|
| pubmed:volume |
88
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
2433-41
|
| pubmed:dateRevised |
2009-11-19
|
| pubmed:meshHeading |
pubmed-meshheading:8839833-Alleles,
pubmed-meshheading:8839833-Biological Transport,
pubmed-meshheading:8839833-Blood Platelets,
pubmed-meshheading:8839833-Cell Line,
pubmed-meshheading:8839833-Cloning, Molecular,
pubmed-meshheading:8839833-Cysteine,
pubmed-meshheading:8839833-DNA Mutational Analysis,
pubmed-meshheading:8839833-Endoplasmic Reticulum,
pubmed-meshheading:8839833-Female,
pubmed-meshheading:8839833-Genes, Dominant,
pubmed-meshheading:8839833-Haplotypes,
pubmed-meshheading:8839833-Heterozygote,
pubmed-meshheading:8839833-Humans,
pubmed-meshheading:8839833-Male,
pubmed-meshheading:8839833-Pedigree,
pubmed-meshheading:8839833-Point Mutation,
pubmed-meshheading:8839833-Protein Structure, Tertiary,
pubmed-meshheading:8839833-Pseudogenes,
pubmed-meshheading:8839833-RNA, Messenger,
pubmed-meshheading:8839833-Recombinant Fusion Proteins,
pubmed-meshheading:8839833-Sequence Homology, Nucleic Acid,
pubmed-meshheading:8839833-von Willebrand Diseases,
pubmed-meshheading:8839833-von Willebrand Factor
|
| pubmed:year |
1996
|
| pubmed:articleTitle |
Dominant type 1 von Willebrand disease caused by mutated cysteine residues in the D3 domain of von Willebrand factor.
|
| pubmed:affiliation |
Department of Hematology, University Hospital, Leiden, The Netherlands.
|
| pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
|