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.