{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T04:48:55Z","timestamp":1761540535906},"reference-count":42,"publisher":"American Society of Hematology","issue":"9","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2004,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>In this manuscript, we describe a case of type 2A von Willebrand disease (VWD) caused by the novel heterozygous G&amp;gt;A transition at nucleotide 3538, which should result in the putative, nonconservative substitution of G1180R. This mutation was reproduced by site-directed mutagenesis; however, the recombinant mutant protein was efficiently secreted from cells and assembled correctly into multimers. Because the substitution is located at the last nucleotide of exon 26, the patient's platelet von Willebrand factor (VWF) mRNA was analyzed and 3 transcripts were observed: the normal transcript without the 3538G&amp;gt;A transition, a transcript with the in-frame deletion of exon 26, and a transcript with the in-frame deletions of exons 23 and 26. These deletion VWF cDNA constructs were created and the resulting recombinant proteins were analyzed following transfection into COS-7 cells. Cotransfection results demonstrate that the exon-skipped transcripts led to intracellular retention, and the levels of VWF antigen (VWF:Ag) produced by these constructs were as follows: del23\/26&amp;lt;del26&amp;lt; G1180R\u2264wild type. The homozygous exon-skipped transcripts show the presence of only the lowest molecular weight multimers. The G&amp;gt;A transition at nucleotide (nt) 3538 does not result in the expression of the G1180R missense mutation, but rather leads to exon skipping, which is the pathogenic basis of the patient's phenotype. This is the first report of a coding region mutation resulting in the skipping of 2 nonadjacent exons. (Blood. 2004;104:2739-2745)<\/jats:p>","DOI":"10.1182\/blood-2003-12-4286","type":"journal-article","created":{"date-parts":[[2004,6,30]],"date-time":"2004-06-30T00:53:31Z","timestamp":1088556811000},"page":"2739-2745","update-policy":"http:\/\/dx.doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":12,"title":["A novel type 2A von Willebrand factor mutation located at the last nucleotide of exon 26 (3538G&amp;gt;A) causes skipping of 2 nonadjacent exons"],"prefix":"10.1182","volume":"104","author":[{"given":"Paula D.","family":"James","sequence":"first","affiliation":[{"name":"From the Department of Pathology and Molecular Medicine Queen's University, Kingston, ON; and the Departments of Biochemistry and Molecular Biology and Medicine, Pediatrics and Oncology, University of Calgary, Calgary, AB."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lee A.","family":"O'Brien","sequence":"additional","affiliation":[{"name":"From the Department of Pathology and Molecular Medicine Queen's University, Kingston, ON; and the Departments of Biochemistry and Molecular Biology and Medicine, Pediatrics and Oncology, University of Calgary, Calgary, AB."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carol A.","family":"Hegadorn","sequence":"additional","affiliation":[{"name":"From the Department of Pathology and Molecular Medicine Queen's University, Kingston, ON; and the Departments of Biochemistry and Molecular Biology and Medicine, Pediatrics and Oncology, University of Calgary, Calgary, AB."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Colleen R. P.","family":"Notley","sequence":"additional","affiliation":[{"name":"From the Department of Pathology and Molecular Medicine Queen's University, Kingston, ON; and the Departments of Biochemistry and Molecular Biology and Medicine, Pediatrics and Oncology, University of Calgary, Calgary, AB."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gary D.","family":"Sinclair","sequence":"additional","affiliation":[{"name":"From the Department of Pathology and Molecular Medicine Queen's University, Kingston, ON; and the Departments of Biochemistry and Molecular Biology and Medicine, Pediatrics and Oncology, University of Calgary, Calgary, AB."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christine","family":"Hough","sequence":"additional","affiliation":[{"name":"From the Department of Pathology and Molecular Medicine Queen's University, Kingston, ON; and the Departments of Biochemistry and Molecular Biology and Medicine, Pediatrics and Oncology, University of Calgary, Calgary, AB."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Man-Chiu","family":"Poon","sequence":"additional","affiliation":[{"name":"From the Department of Pathology and Molecular Medicine Queen's University, Kingston, ON; and the Departments of Biochemistry and Molecular Biology and Medicine, Pediatrics and Oncology, University of Calgary, Calgary, AB."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Lillicrap","sequence":"additional","affiliation":[{"name":"From the Department of Pathology and Molecular Medicine Queen's University, Kingston, ON; and the Departments of Biochemistry and Molecular Biology and Medicine, Pediatrics and Oncology, University of Calgary, Calgary, AB."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"234","reference":[{"key":"2020021300192571700_REF1","doi-asserted-by":"crossref","unstructured":"Rodeghiero F, Castaman G, Dini E. 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