{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T05:00:12Z","timestamp":1761541212706,"version":"3.37.3"},"reference-count":43,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2014,8,8]],"date-time":"2014-08-08T00:00:00Z","timestamp":1407456000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100003246","name":"Nederlandse Organisatie voor Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["91209006"],"award-info":[{"award-number":["91209006"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Br J Haematol"],"published-print":{"date-parts":[[2014,11]]},"abstract":"<jats:title>Summary<\/jats:title><jats:p>Von Willebrand disease (<jats:styled-content style=\"fixed-case\">VWD<\/jats:styled-content>) is a bleeding disorder characterized by reduced plasma von Willebrand factor (<jats:styled-content style=\"fixed-case\">VWF<\/jats:styled-content>) levels or functionally abnormal <jats:styled-content style=\"fixed-case\">VWF<\/jats:styled-content>. Low <jats:styled-content style=\"fixed-case\">VWF<\/jats:styled-content> plasma levels in <jats:styled-content style=\"fixed-case\">VWD<\/jats:styled-content> patients are the result of mutations in the <jats:italic><jats:styled-content style=\"fixed-case\">VWF<\/jats:styled-content><\/jats:italic> gene that lead to decreased synthesis, impaired secretion, increased clearance or a combination thereof. However, expression studies of variants located in the A domains of <jats:styled-content style=\"fixed-case\">VWF<\/jats:styled-content> are limited. We therefore characterized the biosynthesis of <jats:styled-content style=\"fixed-case\">VWF<\/jats:styled-content> mutations, located in the <jats:styled-content style=\"fixed-case\">VWF<\/jats:styled-content> A1\u2013A3 domains, that were found in families diagnosed with <jats:styled-content style=\"fixed-case\">VWD<\/jats:styled-content>. Human Embryonic Kidney 293 (<jats:styled-content style=\"fixed-case\">HEK<\/jats:styled-content>293) cells were transiently transfected with plasmids encoding full\u2010length wild\u2010type <jats:styled-content style=\"fixed-case\">VWF<\/jats:styled-content> or mutant <jats:styled-content style=\"fixed-case\">VWF<\/jats:styled-content>. Six mutations in the A1\u2013A3 domains were expressed. We found that all mutants, except one, showed impaired formation of elongated pseudo\u2010Weibel\u2010Palade bodies (<jats:styled-content style=\"fixed-case\">WPB<\/jats:styled-content>). In addition, two mutations also showed reduced numbers of pseudo\u2010<jats:styled-content style=\"fixed-case\">WPB<\/jats:styled-content>, even in the heterozygous state, and increased endoplasmic reticulum retention, which is in accordance with the impaired regulated secretion seen in patients. Regulated secretion upon stimulation of transfected cells reproduced the <jats:italic>in vivo<\/jats:italic> situation, indicating that <jats:styled-content style=\"fixed-case\">HEK<\/jats:styled-content>293 cells expressing <jats:styled-content style=\"fixed-case\">VWF<\/jats:styled-content> variants found in patients with <jats:styled-content style=\"fixed-case\">VWD<\/jats:styled-content> can be used to properly assess defects in regulated secretion.<\/jats:p>","DOI":"10.1111\/bjh.13074","type":"journal-article","created":{"date-parts":[[2014,8,8]],"date-time":"2014-08-08T10:58:06Z","timestamp":1407495486000},"page":"529-540","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Storage and secretion of naturally occurring von Willebrand factor A domain variants"],"prefix":"10.1111","volume":"167","author":[{"given":"Dafna J.","family":"Groeneveld","sequence":"first","affiliation":[{"name":"Einthoven Laboratory for Experimental Vascular Medicine Department of Thrombosis and Hemostasis Leiden University Medical Centre Leiden The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiong\u2010Wei","family":"Wang","sequence":"additional","affiliation":[{"name":"Einthoven Laboratory for Experimental Vascular Medicine Department of Thrombosis and Hemostasis Leiden University Medical Centre Leiden The Netherlands"},{"name":"Department of Surgery Cardiovascular Research Institute (CVRI) National University Heart Centre Singapore (NUHCS) National University Singapore (NUS) Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marjon J.","family":"Mourik","sequence":"additional","affiliation":[{"name":"Department of Molecular Cell Biology Leiden University Medical Centre Leiden The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard J.","family":"Dirven","sequence":"additional","affiliation":[{"name":"Einthoven Laboratory for 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