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// Jose Navarro-Fernandez 1, * , Maria Eugenia de la Morena-Barrio 1, * , Emma Martinez-Alonso 2 , Ingunn Dybedal 3 , Mara Toderici 1 , Nataliya Bohdan 1 , Antonia Minano 1 , Ketil Heimdal 4 , Ulrich Abildgaard 3 , Jose Angel Martinez-Menarguez 2 , Javier Corral 1 and Vicente Vicente 1 1 Servicio de Hematologia y Oncologia Medica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonacion, Universidad de Murcia, IMIB-Arrixaca, CIBERER, Murcia, Spain 2 Department of Cellular Biology and Histology, Faculty of Medicine, University of Murcia, Murcia, Spain 3 Department of Haematology, Oslo University Hospital, Oslo, Norway 4 Department of Medical Genetics, Oslo University Hospital, Oslo, Norway * These authors have contributed equally to this work Correspondence to: Javier Corral, email: javier.corral@carm.es Keywords: antithrombin; thrombosis; initiation codon; translation Received: November 30, 2017 Accepted: July 31, 2018 Published: September 04, 2018 ABSTRACT Nature is always the best inspiration for basic research. A family with severe thrombosis and antithrombin deficiency, the strongest anticoagulant, carried a new mutation affecting the translation-start codon of SERPINC1 , the gene encoding antithrombin. Expression of this variant in a eukaryotic cell system produced three different antithrombins. Two downstream methionines were used as alternative initiation codons, generating highly expressed small aglycosylated antithrombins with cytoplasmic localization. Wild-type antithrombin was generated by the use of the mutated AUU as initiation codon. Actually, any codon except for the three stop codons might be used to initiate translation in this strong Kozak context. We show unexpected consequences of natural mutations affecting translation-start codons. Downstream alternative initiation AUG codons may be used when the start codon is mutated, generating smaller molecules with potential different cell localization, biochemical features and unexplored consequences. Additionally, our data further support the use of other codons apart from AUG for initiation of translation in eukaryotes. |
