{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:47:51Z","timestamp":1790729271413,"version":"4.1.0"},"reference-count":30,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2014,3,7]],"date-time":"2014-03-07T00:00:00Z","timestamp":1394150400000},"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":[[2014,5]]},"abstract":"<jats:title>Summary<\/jats:title><jats:p>About 10% of mutations in haemophilia A cases generate a premature termination codon in the factor VIII gene (<jats:italic>F8<\/jats:italic>). Upon therapeutic FVIII substitution, it was noted that the risk of developing inhibitors is higher when the nonsense mutation is located in the light chain (LC) of the factor VIII (FVIII) protein than in the heavy chain (HC). We analysed the impact of six different nonsense mutations distributed over the six FVIII domains on recombinant FVIII expression to elucidate the process of inhibitor formation in haemophilic patients. Full\u2010length <jats:italic>F8 <\/jats:italic><jats:styled-content style=\"fixed-case\">mRNA<\/jats:styled-content> was transcribed from all constructs despite the presence of nonsense mutations. Polyclonal antigen assays revealed high antigen levels in transfection experiments with constructs truncated in LC whereas low antigen was detected from constructs truncated in HC. Those results were supported by FVIII localization experiments. These findings suggest that <jats:italic>F8<\/jats:italic> transcription occurs in a usual way despite nonsense mutations, whereas translation appears to be interrupted by the premature stop codon. We hypothesize that the inclusion of the B domain enables proteins truncated in LC to accumulate in the ER. Proteins truncated in HC are mainly degraded or may pass through the ER and be secreted into the blood circulation, thus presumably preventing inhibitor formation after therapeutic FVIII substitution. The LC is known to have higher immunogenicity than the HC. Moreover, translation of the <jats:italic>F8B<\/jats:italic> gene comprising <jats:italic>F8<\/jats:italic> exons 23\u201326 may be dependent on the position of the premature stop codon and thus contributes to the immune response of truncated FVIII proteins.<\/jats:p>","DOI":"10.1111\/hae.12388","type":"journal-article","created":{"date-parts":[[2014,3,7]],"date-time":"2014-03-07T08:28:40Z","timestamp":1394180920000},"source":"Crossref","is-referenced-by-count":6,"title":["Expression studies of mutant factor <scp>VIII<\/scp> alleles with premature termination codons with regard to inhibitor formation"],"prefix":"10.1111","volume":"20","author":[{"given":"M. A.","family":"Zimmermann","sequence":"first","affiliation":[{"name":"Department of Human Genetics University of W\u00fcrzburg W\u00fcrzburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Oldenburg","sequence":"additional","affiliation":[{"name":"Institute of Experimental Haematology and Transfusion Medicine University of Bonn Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. R.","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Department of Human Genetics University of W\u00fcrzburg W\u00fcrzburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Rost","sequence":"additional","affiliation":[{"name":"Department of Human Genetics University of W\u00fcrzburg W\u00fcrzburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2014,3,7]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1532\/IJH97.06012"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg1617"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1136\/mp.55.2.127"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2516.2004.01005.x"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2008.03125.x"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2011.04574.x"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/26.1.216"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2516.2003.00780.x"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-09-379453"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00583-9"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2004.03.003"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/bfgp\/els051"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-009-0177-1"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1538-7836.2003.00013.x"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.83.16.5939"},{"key":"e_1_2_8_17_1","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1055\/s-0038-1646161","article-title":"Factor VIII structure and function","volume":"70","author":"Fay PJ","year":"1993","journal-title":"Thromb Haemost"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/312337a0"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2516.2009.02026.x"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1052"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.24.14505"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.4.1935"},{"key":"e_1_2_8_23_1","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1182\/blood.V95.1.156","article-title":"A human antibody directed to the factor VIII C1 domain inhibits factor VIII cofactor activity and binding to von Willebrand factor","volume":"95","author":"Jacquemin M","year":"2000","journal-title":"Blood"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1097\/00001721-199003000-00003"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1160\/TH08-08-0508"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0037-1615061"},{"key":"e_1_2_8_27_1","doi-asserted-by":"crossref","DOI":"10.1055\/s-2002-32665","volume-title":"New Characteristics of Anti\u2010Factor VIII Inhibitor Antibody Epitopes and Unusual Immune Responses to Factor VIII","author":"Scandella D","year":"2002"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0888-7543(05)80155-7"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/8.7.1291"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1351-8216.2001.00134.x"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-01-132639"}],"container-title":["Haemophilia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fhae.12388","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/hae.12388","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,24]],"date-time":"2023-09-24T08:15:30Z","timestamp":1695543330000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/hae.12388"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,3,7]]},"references-count":30,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2014,5]]}},"alternative-id":["10.1111\/hae.12388"],"URL":"https:\/\/doi.org\/10.1111\/hae.12388","archive":["Portico"],"relation":{},"ISSN":["1351-8216","1365-2516"],"issn-type":[{"value":"1351-8216","type":"print"},{"value":"1365-2516","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,3,7]]}}}