{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T13:07:30Z","timestamp":1792156050301,"version":"4.4.0"},"reference-count":30,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2016,10,26]],"date-time":"2016-10-26T00:00:00Z","timestamp":1477440000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Haemophilia"],"published-print":{"date-parts":[[2016,11]]},"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>We characterized five patients affected with von Willebrand disease (<jats:styled-content style=\"fixed-case\">VWD<\/jats:styled-content>) carrying the p.Arg1379Cys mutation. One was diagnosed as <jats:styled-content style=\"fixed-case\">VWD<\/jats:styled-content> type 1 and four as type 2M. The 2M patients also have the variant p.Ala1377Val <jats:italic>in cis<\/jats:italic> with p.Arg1379Cys.<\/jats:p><\/jats:sec><jats:sec><jats:title>Aim<\/jats:title><jats:p>To evaluate the role of p.Ala1377Val and p.Arg1379Cys von Willebrand factor (<jats:styled-content style=\"fixed-case\">VWF<\/jats:styled-content>) variants to explain patients' phenotype.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Conventional phenotype tests were used to evaluate patients' plasma and platelets. Direct sequence analysis of exon 28 was carried out. The allele frequency of p.Ala1377Val was evaluated using online database. pc<jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content>3.1\u2010<jats:styled-content style=\"fixed-case\">VWF<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">WT<\/jats:styled-content> and mutant (A1377V, R1379C and A1377V\u2010R1379C) expression vectors were transiently transfected in <jats:styled-content style=\"fixed-case\">HEK<\/jats:styled-content>293 cells. The capacity of <jats:styled-content style=\"fixed-case\">WT<\/jats:styled-content> and mutant recombinant (r)<jats:styled-content style=\"fixed-case\">VWF<\/jats:styled-content> (along with patients' plasma <jats:styled-content style=\"fixed-case\">VWF<\/jats:styled-content>) to bind glycoprotein Ib\u03b1 (GpIb\u03b1) were evaluated, using two <jats:styled-content style=\"fixed-case\">ELISA<\/jats:styled-content> assays. One with a wild\u2010type (<jats:styled-content style=\"fixed-case\">WT<\/jats:styled-content>) recombinant (r)GpIb\u03b1 at increasing ristocetin concentrations (from 0 to 1.50 mg <jats:styled-content style=\"fixed-case\">mL<\/jats:styled-content><jats:sup>\u22121<\/jats:sup>) and the other with a gain\u2010of\u2010function mutant <jats:styled-content style=\"fixed-case\">rGpI<\/jats:styled-content>b\u03b1 (<jats:styled-content style=\"fixed-case\">VWF<\/jats:styled-content>:<jats:styled-content style=\"fixed-case\">GPI<\/jats:styled-content>bM).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The substitution c.4130C&gt;T (p.Ala1377Val) was reported as rare variant in online databases. At 0.25 mg <jats:styled-content style=\"fixed-case\">mL<\/jats:styled-content><jats:sup>\u22121<\/jats:sup> of ristocetin, <jats:styled-content style=\"fixed-case\">WT<\/jats:styled-content>, A1377V and R1379C showed 6, 7.5 and 12\u2010fold increased binding to <jats:styled-content style=\"fixed-case\">rGpI<\/jats:styled-content>b\u03b1, respectively. A1377V\u2010R1379C <jats:styled-content style=\"fixed-case\">rVWF<\/jats:styled-content> showed no increased binding to <jats:styled-content style=\"fixed-case\">rGpI<\/jats:styled-content>b\u03b1 at the same ristocetin concentration and reached the highest binding, of only 3\u2010fold increased, at 1.50 mg <jats:styled-content style=\"fixed-case\">mL<\/jats:styled-content><jats:sup>\u22121<\/jats:sup> of ristocetin. The <jats:styled-content style=\"fixed-case\">VWF<\/jats:styled-content>:<jats:styled-content style=\"fixed-case\">GPI<\/jats:styled-content>bM showed strongly reduced values for the A1377V\u2010R1379C <jats:styled-content style=\"fixed-case\">rVWF<\/jats:styled-content> and the 2M patients' plasma.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our study showed that the presence of both p.Ala1377Val and p.Arg1379Cys mutations (synergistic effect) abolishes the binding of <jats:styled-content style=\"fixed-case\">rVWF<\/jats:styled-content> to <jats:styled-content style=\"fixed-case\">rGpI<\/jats:styled-content>b\u03b1, explaining patients' 2M phenotype.<\/jats:p><\/jats:sec>","DOI":"10.1111\/hae.13084","type":"journal-article","created":{"date-parts":[[2016,10,27]],"date-time":"2016-10-27T01:06:42Z","timestamp":1477530402000},"source":"Crossref","is-referenced-by-count":9,"title":["von Willebrand disease type 1 mutation p.Arg1379Cys and the variant p.Ala1377Val synergistically determine a 2M phenotype in four Italian patients"],"prefix":"10.1111","volume":"22","author":[{"given":"M. T.","family":"Pagliari","sequence":"first","affiliation":[{"name":"Angelo Bianchi Bonomi Hemophilia and Thrombosis Center Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and Fondazione Luigi Villa Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L.","family":"Baronciani","sequence":"additional","affiliation":[{"name":"Angelo Bianchi Bonomi Hemophilia and Thrombosis Center Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and Fondazione Luigi Villa Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F.","family":"Stufano","sequence":"additional","affiliation":[{"name":"Angelo Bianchi Bonomi Hemophilia and Thrombosis Center Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and Fondazione Luigi Villa Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I.","family":"Garcia\u2010Oya","sequence":"additional","affiliation":[{"name":"Angelo Bianchi Bonomi Hemophilia and Thrombosis Center Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and Fondazione Luigi Villa Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G.","family":"Cozzi","sequence":"additional","affiliation":[{"name":"Angelo Bianchi Bonomi Hemophilia and Thrombosis Center Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and Fondazione Luigi Villa Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F.","family":"Franchi","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology and Transplantation Universit\u00e0 degli Studi di Milano Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F.","family":"Peyvandi","sequence":"additional","affiliation":[{"name":"Angelo Bianchi Bonomi Hemophilia and Thrombosis Center Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and Fondazione Luigi Villa Milan Italy"},{"name":"Department of Pathophysiology and Transplantation Universit\u00e0 degli Studi di Milano Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,10,26]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0037-1613992"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.67.1.395"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V70.4.895.895"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2006.02146.x"},{"key":"e_1_2_8_6_1","first-page":"34","article-title":"Molecular genetics of von Willebrand disease","volume":"1","author":"Mazurier C","year":"1998","journal-title":"Ann Rev Genet"},{"key":"e_1_2_8_7_1","first-page":"414","article-title":"New mutations in exon 28 of the von Willebrand factor gene detected in patients with different types of von Willebrand's disease","volume":"86","author":"Casa\u00f1a P","year":"2001","journal-title":"Haematol"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-11-123695"},{"key":"e_1_2_8_9_1","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1160\/TH08-08-0500","article-title":"Rapid molecular diagnosis of von Willebrand disease by direct sequencing. 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