دورية أكاديمية
Characterization of W1745C and S1783A: 2 novel mutations causing defective collagen binding in the A3 domain of von Willebrand factor.
| العنوان: | Characterization of W1745C and S1783A: 2 novel mutations causing defective collagen binding in the A3 domain of von Willebrand factor. |
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| المؤلفون: | Riddell AF; Katharine Dormandy Haemophilia Centre and Thrombosis Unit, The Royal Free and University College Medical School, London, United Kingdom., Gomez K, Millar CM, Mellars G, Gill S, Brown SA, Sutherland M, Laffan MA, McKinnon TA |
| المصدر: | Blood [Blood] 2009 Oct 15; Vol. 114 (16), pp. 3489-96. Date of Electronic Publication: 2009 Aug 17. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Country of Publication: United States NLM ID: 7603509 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1528-0020 (Electronic) Linking ISSN: 00064971 NLM ISO Abbreviation: Blood Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2021- : [New York] : Elsevier Original Publication: New York, Grune & Stratton [etc.] |
| مواضيع طبية MeSH: | Mutation, Missense*, Collagen Type I/*metabolism , Collagen Type II/*metabolism , Hemorrhage/*metabolism , Protein Multimerization/*genetics , von Willebrand Diseases/*metabolism , von Willebrand Factor/*metabolism, Amino Acid Substitution ; Binding Sites/genetics ; Cell Line ; Collagen Type I/genetics ; Collagen Type II/genetics ; Family ; Female ; Gene Expression ; Hemorrhage/genetics ; Humans ; Male ; Mutagenesis, Site-Directed ; Protein Binding/genetics ; Protein Structure, Tertiary/genetics ; Recombinant Proteins/economics ; Recombinant Proteins/metabolism ; von Willebrand Diseases/classification ; von Willebrand Diseases/genetics ; von Willebrand Factor/genetics |
| مستخلص: | Investigation of 3 families with bleeding symptoms demonstrated a defect in the collagen-binding activity of von Willebrand factor (VWF) in association with a normal VWF multimeric pattern. Genetic analysis showed affected persons to be heterozygous for mutations in the A3 domain of VWF: S1731T, W1745C, and S1783A. One person showed compound heterozygosity for W1745C and R760H. W1745C and S1783A have not been reported previously. The mutations were reproduced by site-directed mutagenesis and mutant VWF expressed in HEK293T cells. Collagen-binding activity measured by immunosorbent assay varied according to collagen type: W1745C and S1783A were associated with a pronounced binding defect to both type I and type III collagen, whereas the principal abnormality in S1731T patients was a reduction in binding to type I collagen only. The multimer pattern and distribution of mutant proteins were indistinguishable from wild-type recombinant VWF, confirming that the defect in collagen binding resulted from the loss of affinity at the binding site and not impairment of high-molecular-weight multimer formation. Our findings demonstrate that mutations causing an abnormality in the binding of VWF to collagen may contribute to clinically significant bleeding symptoms. We propose that isolated collagen-binding defects are classified as a distinct subtype of von Willebrand disease. |
| المشرفين على المادة: | 0 (Collagen Type I) 0 (Collagen Type II) 0 (Recombinant Proteins) 0 (von Willebrand Factor) |
| تواريخ الأحداث: | Date Created: 20090819 Date Completed: 20091106 Latest Revision: 20210206 |
| رمز التحديث: | 20240628 |
| DOI: | 10.1182/blood-2008-10-184317 |
| PMID: | 19687512 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1528-0020 |
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| DOI: | 10.1182/blood-2008-10-184317 |