Biochemical and cellular consequences of the antithrombin p.Met1? mutation identified in a severe thrombophilic family
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José Navarro-Fernández1,*, María Eugenia de la Morena-Barrio1,*, Emma Martínez-Alonso2, Ingunn Dybedal3, Mara Toderici1, Nataliya Bohdan1, Antonia Miñano1, Ketil Heimdal4, Ulrich Abildgaard3, José Ángel Martínez-Menárguez2, Javier Corral1 and Vicente Vicente1
1Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Arrixaca, CIBERER, Murcia, Spain
2Department of Cellular Biology and Histology, Faculty of Medicine, University of Murcia, Murcia, Spain
3Department of Haematology, Oslo University Hospital, Oslo, Norway
4Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
*These authors have contributed equally to this work
Javier Corral, email: email@example.com
Keywords: antithrombin; thrombosis; initiation codon; translation
Received: November 30, 2017 Accepted: July 31, 2018 Published: September 04, 2018
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.
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