Journal
JCI INSIGHT
Volume 7, Issue 19, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.161430
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Funding
- Instituto de Salud Carlos III
- Fondo Europeo de Desarrollo Regional [PI18/00598, PI21/00174]
- Fundacion Seneca [19873/GERM/15]
- Rio Hortega fellowship [CM20/00094]
- Fundacion Seneca
- Predoctoral Contracts for Training in Health Research (PFIS) contract
- Postdoctoral Ramon y Casjal contract at University of Murcia
- MRC [MCMB MR/V028669/1]
- Alpha1 Foundation [830153]
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This study characterized the biological and clinical impact of variants involving C-terminal antithrombin and found that the clinical phenotypes of these genetic changes are consistent with their dominant-negative effects.
Antithrombin, a major endogenous anticoagulant, is a serine protease inhibitor (serpin). We characterized the biological and clinical impact of variants involving C-terminal antithrombin. We performed comprehensive molecular, cellular, and clinical characterization of patients with C-terminal antithrombin variants from a cohort of 444 unrelated individuals with confirmed antithrombin deficiency. We identified 17 patients carrying 12 C-terminal variants, 5 of whom had the p.Arg445Serfs*17 deletion. Five missense variants caused qualitative deficiency, and 7, including 4 insertion-deletion variants, induced severe quantitative deficiency, particularly p.Arg445Serfs*17 (antithrombin <40%). This +1 frameshift variant had a molecular size similar to that of WT antithrombin but possessed a different C-terminus. Morphologic and cotransfection experiments showed that recombinant p.Arg445Serfs*17 was retained at the endoplasmic reticulum and had a dominant-negative effect on WT antithrombin. Characterization of different 1+ frameshift, aberrant C-terminal variants revealed that protein secretion was determined by frameshift site. The introduction of Pro441 in the aberrant C-terminus, shared by 5 efficiently secreted variants, partially rescued p.Arg445Serfs*17 secretion. C-terminal antithrombin mutants have notable heterogeneity, related to variant type and localization. Aberrant C-terminal variants caused by 1+ frameshift, with similar size as WT antithrombin, may be secreted or not, depending on frameshift site. The severe clinical phenotypes of these genetic changes are consistent with their dominant-negative effects.
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