{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T09:30:11Z","timestamp":1790501411236,"version":"4.1.0"},"reference-count":37,"publisher":"American Society of Hematology","issue":"7","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2001,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Dimerization defects of von Willebrand factor (vWF) protomers underlie von Willebrand disease (vWD) type 2A, subtype IID (vWD 2A\/IID), and corresponding mutations have been identified at the 3\u2032 end of the vWF gene in exon 52. This study identified and expressed 2 additional mutations in this region, a homozygous defect in a patient with vWD type 3 (C2754W) and a heterozygous frameshift mutation (8566delC) in a patient with vWD type 2A, subtype IIE. Both mutations involve cysteine residues that we propose are possibly essential for dimerization. To prove this hypothesis, transient recombinant expression of each of the 2 mutations introduced in the carboxy-terminal vWF fragment II and in the complete vWF complementary DNA, respectively, were carried out in COS-7 cells and compared with expression of vWD 2A\/IID mutation C2773R and the wild-type (WT) sequence in COS-7 cells. Recombinant WT vWF fragment II assembled correctly into a dimer, whereas recombinant mutant fragments were monomeric. Homozygous expression of recombinant mutant full-length vWF resulted in additional dimers, probably through disulfide bonding at the amino-terminal multimerization site, whereas recombinant WT vWF correctly assembled into multimers. Coexpression of recombinant mutant and recombinant WT vWF reproduced the multimer patterns observed in heterozygous individuals. Our results suggest that a common defect of vWF biosynthesis\u2014lack of vWF dimerization\u2014may cause diverse types and subtypes of vWD. We also confirmed previous studies that found that disulfide bonding at the vWF amino-terminal is independent of dimerization at the vWF carboxy-terminal.<\/jats:p>","DOI":"10.1182\/blood.v97.7.2059","type":"journal-article","created":{"date-parts":[[2002,7,27]],"date-time":"2002-07-27T12:46:47Z","timestamp":1027774007000},"page":"2059-2066","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":62,"title":["Expression and characterization of von Willebrand factor dimerization defects in different types of von Willebrand disease"],"prefix":"10.1182","volume":"97","author":[{"given":"Reinhard","family":"Schneppenheim","sequence":"first","affiliation":[{"name":"From Pediatric Hematology and Oncology, University Children's Hospital, Hamburg, Germany; Lab Association Keeser, Arndt and Partners, Coagulation Lab, Hamburg, Germany; Searle\/Monsanto, Investigative and Discovery Pathology, St Louis, MO; the Scripps Research Institute, La Jolla, CA; and the Institute of Experimental Hematology and Transfusion Medicine, University of Bonn, Bonn, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich","family":"Budde","sequence":"additional","affiliation":[{"name":"From Pediatric Hematology and Oncology, University Children's Hospital, Hamburg, Germany; Lab Association Keeser, Arndt and Partners, Coagulation Lab, Hamburg, Germany; Searle\/Monsanto, Investigative and Discovery Pathology, St Louis, MO; the Scripps Research Institute, La Jolla, CA; and the Institute of Experimental Hematology and Transfusion Medicine, University of Bonn, Bonn, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Obser","sequence":"additional","affiliation":[{"name":"From Pediatric Hematology and Oncology, University Children's Hospital, Hamburg, Germany; Lab Association Keeser, Arndt and Partners, Coagulation Lab, Hamburg, Germany; Searle\/Monsanto, Investigative and Discovery Pathology, St Louis, MO; the Scripps Research Institute, La Jolla, CA; and the Institute of Experimental Hematology and Transfusion Medicine, University of Bonn, Bonn, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline","family":"Brassard","sequence":"additional","affiliation":[{"name":"From Pediatric Hematology and Oncology, University Children's Hospital, Hamburg, Germany; Lab Association Keeser, Arndt and Partners, Coagulation Lab, Hamburg, Germany; Searle\/Monsanto, Investigative and Discovery Pathology, St Louis, MO; the Scripps Research Institute, La Jolla, CA; and the Institute of Experimental Hematology and Transfusion Medicine, University of Bonn, Bonn, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerstin","family":"Mainusch","sequence":"additional","affiliation":[{"name":"From Pediatric Hematology and Oncology, University Children's Hospital, Hamburg, Germany; Lab Association Keeser, Arndt and Partners, Coagulation Lab, Hamburg, Germany; Searle\/Monsanto, Investigative and Discovery Pathology, St Louis, MO; the Scripps Research Institute, La Jolla, CA; and the Institute of Experimental Hematology and Transfusion Medicine, University of Bonn, Bonn, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zaverio M.","family":"Ruggeri","sequence":"additional","affiliation":[{"name":"From Pediatric Hematology and Oncology, University Children's Hospital, Hamburg, Germany; Lab Association Keeser, Arndt and Partners, Coagulation Lab, Hamburg, Germany; Searle\/Monsanto, Investigative and Discovery Pathology, St Louis, MO; the Scripps Research Institute, La Jolla, CA; and the Institute of Experimental Hematology and Transfusion Medicine, University of Bonn, Bonn, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonja","family":"Schneppenheim","sequence":"additional","affiliation":[{"name":"From Pediatric Hematology and Oncology, University Children's Hospital, Hamburg, Germany; Lab Association Keeser, Arndt and Partners, Coagulation Lab, Hamburg, Germany; Searle\/Monsanto, Investigative and Discovery Pathology, St Louis, MO; the Scripps Research Institute, La Jolla, CA; and the Institute of Experimental Hematology and Transfusion Medicine, University of Bonn, Bonn, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rainer","family":"Schwaab","sequence":"additional","affiliation":[{"name":"From Pediatric Hematology and Oncology, University Children's Hospital, Hamburg, Germany; Lab Association Keeser, Arndt and Partners, Coagulation Lab, Hamburg, Germany; Searle\/Monsanto, Investigative and Discovery Pathology, St Louis, MO; the Scripps Research Institute, La Jolla, CA; and the Institute of Experimental Hematology and Transfusion Medicine, University of Bonn, Bonn, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Oldenburg","sequence":"additional","affiliation":[{"name":"From Pediatric Hematology and Oncology, University Children's Hospital, Hamburg, Germany; Lab Association Keeser, Arndt and Partners, Coagulation Lab, Hamburg, Germany; Searle\/Monsanto, Investigative and Discovery Pathology, St Louis, MO; the Scripps Research Institute, La Jolla, CA; and the Institute of Experimental Hematology and Transfusion Medicine, University of Bonn, Bonn, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"key":"2020021217274287700_B1","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1172\/JCI112974","article-title":"Gene deletions correlate with the development of alloantibodies in von Willebrand disease.","volume":"79","author":"Shelton-Inloes","year":"1987","journal-title":"J Clin 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