Two SERPINC1 variants affecting N-glycosylation of Asn224 cause severe thrombophilia not detected by functional assays
| dc.rights.license | open | en_US |
| dc.contributor.author | DE LA MORENA-BARRIO, Maria Eugenia | |
| dc.contributor.author | SUCHON, Pierre | |
| dc.contributor.author | JACOBSEN, Eva Marie | |
| dc.contributor.author | IVERSEN, Nina | |
| dc.contributor.author | MINANO, Antonia | |
| dc.contributor.author | DE LA MORENA-BARRIO, Belen | |
| dc.contributor.author | BRAVO-PEREZ, Carlos | |
| dc.contributor.author | PADILLA, Jose | |
| dc.contributor.author | CIFUENTES, Rosa | |
| dc.contributor.author | ASENJO, Susana | |
| dc.contributor.author | DELEUZE, Jean Francois | |
| hal.structure.identifier | Bordeaux population health [BPH] | |
| dc.contributor.author | TREGOUET, David-Alexandre | |
| dc.contributor.author | LOZANO, Maria Luisa | |
| dc.contributor.author | VICENTE, Vicente | |
| dc.contributor.author | SANDSET, Per Morten | |
| dc.contributor.author | MORANGE, Pierre Emmanuel | |
| dc.contributor.author | CORRAL, Javier | |
| dc.date.accessioned | 2022-10-17T11:55:15Z | |
| dc.date.available | 2022-10-17T11:55:15Z | |
| dc.date.issued | 2022-07-14 | |
| dc.identifier.issn | 1528-0020 (Electronic) 0006-4971 (Linking) | en_US |
| dc.identifier.uri | https://oskar-bordeaux.fr/handle/20.500.12278/170035 | |
| dc.description.abstractEn | Antithrombin deficiency, the most severe congenital thrombophilia, might be underestimated, as some pathogenic variants are not detected by routine functional methods. We have identified 2 new SERPINC1 variants, p.Glu227Lys and p.Asn224His, in 4 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 SERPINC1 based on a single functional positive finding supporting deficiency. The 2 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 for 1 hour at 41°C. Moreover, the β glycoform of the variants, lacking 2 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. Our study shows new elements involved in the regulation of N-glycosylation, a key posttranslational modification that, according to our results, affects folding, secretion, and function, providing new evidence of the pathogenic consequence of an incorrect N-glycosylation of antithrombin. This study supports that antithrombin deficiency is underestimated and encourages the development of new functional and genetic tests to diagnose this severe thrombophilia. | |
| dc.description.sponsorship | Medical Genomics - ANR-10-LABX-0013 | en_US |
| dc.language.iso | EN | en_US |
| dc.rights | Attribution-NonCommercial-NoDerivs 3.0 United States | * |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/us/ | * |
| dc.title.en | Two SERPINC1 variants affecting N-glycosylation of Asn224 cause severe thrombophilia not detected by functional assays | |
| dc.type | Article de revue | en_US |
| dc.identifier.doi | 10.1182/blood.2021014708 | en_US |
| dc.subject.hal | Sciences du Vivant [q-bio]/Santé publique et épidémiologie | en_US |
| dc.identifier.pubmed | 35486842 | en_US |
| bordeaux.journal | Blood | en_US |
| bordeaux.page | 140-151 | en_US |
| bordeaux.volume | 140 | en_US |
| bordeaux.hal.laboratories | Bordeaux Population Health Research Center (BPH) - UMR 1219 | en_US |
| bordeaux.issue | 2 | en_US |
| bordeaux.institution | Université de Bordeaux | en_US |
| bordeaux.institution | INSERM | en_US |
| bordeaux.team | ELEANOR_BPH | en_US |
| bordeaux.peerReviewed | oui | en_US |
| bordeaux.inpress | non | en_US |
| bordeaux.identifier.funderID | Agence Nationale de la Recherche | en_US |
| hal.identifier | hal-03800816 | |
| hal.version | 1 | |
| hal.export | false | |
| dc.rights.cc | Pas de Licence CC | en_US |
| bordeaux.COinS | ctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=Blood&rft.date=2022-07-14&rft.volume=140&rft.issue=2&rft.spage=140-151&rft.epage=140-151&rft.eissn=1528-0020%20(Electronic)%200006-4971%20(Linking)&rft.issn=1528-0020%20(Electronic)%200006-4971%20(Linking)&rft.au=DE%20LA%20MORENA-BARRIO,%20Maria%20Eugenia&SUCHON,%20Pierre&JACOBSEN,%20Eva%20Marie&IVERSEN,%20Nina&MINANO,%20Antonia&rft.genre=article |
