{"doi":"10.1172/jci.insight.161430","title":"Full-length antithrombin frameshift variant with aberrant C-terminus causes endoplasmic reticulum retention with a dominant-negative effect","abstract":"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.","journal":"JCI Insight","year":2022,"id":263580,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":13,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9506,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":921172,"name":"Mara Toderici","orcid":null,"position":1,"is_corresponding":false},{"id":867783,"name":"Joseph E. Chambers","orcid":"0000-0003-4675-0053","position":2,"is_corresponding":false},{"id":920585,"name":"José A. Martínez‐Menárguez","orcid":"0000-0002-7268-3328","position":3,"is_corresponding":false},{"id":920586,"name":"Pedro Garrido","orcid":"0000-0003-3447-248X","position":4,"is_corresponding":false},{"id":51920,"name":"Horacio Pérez‐Sánchez","orcid":"0000-0003-4468-7898","position":5,"is_corresponding":false},{"id":920587,"name":"Belén de la Morena‐Barrio","orcid":"0000-0002-6696-7762","position":6,"is_corresponding":false},{"id":530727,"name":"José Padilla","orcid":"0000-0003-1599-7870","position":7,"is_corresponding":false},{"id":531328,"name":"Antonia Miñano","orcid":null,"position":8,"is_corresponding":false},{"id":921173,"name":"Rosa Cifuentes‐Riquelme","orcid":null,"position":9,"is_corresponding":false},{"id":530736,"name":"Vicente Vicente","orcid":"0000-0002-4278-3264","position":10,"is_corresponding":false},{"id":530738,"name":"Marı́a Luisa Lozano","orcid":"0000-0003-3148-7037","position":11,"is_corresponding":false},{"id":812150,"name":"Stefan J. Marciniak","orcid":"0000-0001-8472-7183","position":12,"is_corresponding":false},{"id":530724,"name":"María Eugenia de la Morena‐Barrio","orcid":"0000-0001-7426-4947","position":13,"is_corresponding":false},{"id":530737,"name":"Javier Corral","orcid":"0000-0003-0288-1107","position":14,"is_corresponding":false},{"id":920584,"name":"Carlos Bravo‐Pérez","orcid":"0000-0001-9794-7847","position":0,"is_corresponding":true}],"reference_count":71,"raw_metadata":null,"created_at":"2026-07-19T00:26:33.413850Z","pmid":"36214221","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}