부산대학교 도서관

Antithrombin deficiency, the most severe congenital thrombophilia, might be underestimated, as some pathogenic variants are not detected by routine functional methods. We have identified two new SERPINC1variants, p.Glu227Lys and p.Asn224His, in four unrelated thrombophilic patients with early and recurrent thrombosis that had normal antithrombin activity. In one case, the mutation was identified by whole genome sequencing, while in the 3 remaining cases, the mutation was identified by sequencing SERPINC1based on a single functional positive finding supporting deficiency. The two variants shared a common functional defect, an impaired or null N-glycosylation of Asn224 according to a eukaryotic expression model. Carriers had normal anti-FXa or anti-FIIa activities, but impaired anti-FVIIa activity and a detectable loss of inhibitory function when incubating the plasma 1 hour at 41ºC. Moreover, the beta glycoform of the variants, lacking two N-glycans, had reduced secretion, increased heparin affinity, no inhibitory activity, and a potential dominant negative effect. These results explain the increased thrombin generation observed in carriers. Mutation experiments reflected the role that Lysine residues close to the N-glycosylation sequon have in impairing the efficacy of N-glycosylation.