{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T09:30:41Z","timestamp":1790501441644,"version":"4.1.0"},"reference-count":31,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2018,11,29]],"date-time":"2018-11-29T00:00:00Z","timestamp":1543449600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100002724","name":"University of Sharjah","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100002724","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Br J Haematol"],"published-print":{"date-parts":[[2019,3]]},"abstract":"<jats:title>Summary<\/jats:title><jats:p>We previously reported that von Willebrand Factor gene (<jats:italic><jats:styled-content style=\"fixed-case\">VWF<\/jats:styled-content><\/jats:italic>) conversions are a relatively frequent cause of von Willebrand disease (<jats:styled-content style=\"fixed-case\">VWD<\/jats:styled-content>), however, their molecular pathomechanisms resulting in variant phenotypes is largely unknown. Here, we characterized <jats:italic><jats:styled-content style=\"fixed-case\">VWF<\/jats:styled-content><\/jats:italic> conversions harbouring missense and synonymous mutations, through generating a series of mutant constructs followed by transient expression in 293 cells, and qualitative and quantitative analysis of recombinant <jats:styled-content style=\"fixed-case\">VWF<\/jats:styled-content> (<jats:styled-content style=\"fixed-case\">rVWF<\/jats:styled-content>). The characterization of mutant <jats:styled-content style=\"fixed-case\">rVWF<\/jats:styled-content> showed the critical roles of synonymous variants in the pathogenicity of <jats:italic><jats:styled-content style=\"fixed-case\">VWF<\/jats:styled-content><\/jats:italic> conversions. The gene conversion variants p.Val1229Gly, p.Asn1231Thr, p.Asn1231Ser and p.Ala1464Pro in the absence of synonymous p.Ser1263= and p.Gln1449= showed minimal effect on <jats:styled-content style=\"fixed-case\">rVWF<\/jats:styled-content> synthesis and activity. Interestingly, a construct including the synonymous variants displayed significantly low <jats:styled-content style=\"fixed-case\">rVWF<\/jats:styled-content> expression and activity. The variant p.Pro1266Leu showed gain of <jats:styled-content style=\"fixed-case\">rVWF<\/jats:styled-content> function toward glycoprotein Ib\u03b1; surprisingly, this function was significantly abolished in the presence of gene conversion variants p.Val1229Gly\u2010p.Asn1231Thr. Taken together, our expression studies suggest that synonymous variants in the combination of other gene conversion variants suppress the protein expression, possibly due to defective primary <jats:styled-content style=\"fixed-case\">mRNA<\/jats:styled-content> structure or processing. The variants p.Val1229Gly\u2010p.Asn1231Thr affected the <jats:styled-content style=\"fixed-case\">VWF<\/jats:styled-content> gain of function caused by variant p.Pro1266Leu, probably due to conformational changes in VWF.<\/jats:p>","DOI":"10.1111\/bjh.15709","type":"journal-article","created":{"date-parts":[[2018,11,29]],"date-time":"2018-11-29T08:30:04Z","timestamp":1543480204000},"page":"817-825","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Characterization of <i><scp>VWF<\/scp><\/i> gene conversions causing von Willebrand disease"],"prefix":"10.1111","volume":"184","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6530-6068","authenticated-orcid":false,"given":"Firdos","family":"Ahmad","sequence":"first","affiliation":[{"name":"Sharjah Institute for Medical Research and, College of Medicine University of Sharjah Sharjah UAE"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meganathan","family":"Kannan","sequence":"additional","affiliation":[{"name":"Division of Blood and Vascular Biology Department of Life Sciences School of Basic and Applied Sciences Central University of Tamilnadu Thiruvarur India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Obser","sequence":"additional","affiliation":[{"name":"Department of Pediatric Haematology and Oncology University Medical Centre Eppendorf Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich","family":"Budde","sequence":"additional","affiliation":[{"name":"Medilys Laboratory Coagulation Asklepios Hospital Altona Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonja","family":"Schneppenheim","sequence":"additional","affiliation":[{"name":"Medilys Laboratory Coagulation Asklepios Hospital Altona Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renu","family":"Saxena","sequence":"additional","affiliation":[{"name":"Department of Haematology All India Institute of Medical Sciences New Delhi India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reinhard","family":"Schneppenheim","sequence":"additional","affiliation":[{"name":"Department of Pediatric Haematology and Oncology University Medical Centre Eppendorf Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,11,29]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1160\/TH12-10-0737"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1160\/TH12-07-0475"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/hae.13175"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.511220"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2016.01.008"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg2193"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/molbev\/msx229"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V87.6.2322.bloodjournal8762322"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.12597"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1039\/c004796c"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI112430"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0038864"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.6.2221"},{"key":"e_1_2_7_15_1","first-page":"77","article-title":"A sensitive ristocetin co\u2010factor activity assay with recombinant glycoprotein Ibalpha for the diagnosis of patients with low von Willebrand factor levels","volume":"89","author":"Federici A.B.","year":"2004","journal-title":"Haematologica"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.2005.05660.x"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-09-244327"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2011.046623"},{"key":"e_1_2_7_19_1","first-page":"99","article-title":"Wadding of the axilla in the conservative treatment of cancer of the breast. 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