{"doi":"10.1002/ajh.26076","title":"A novel genetic variant in <scp><i>PTGS1</i></scp> affects N‐glycosylation of cyclooxygenase‐1 causing a dominant‐negative effect on platelet function and bleeding diathesis","abstract":"During platelet activation, arachidonic acid (AA) is released from membrane phospholipids and metabolized to thromboxane A2 (TXA2) through the actions of cyclooxygenase-1 (COX-1) and TXA2 synthase. Note, TXA2 binds to the platelet TXA2 receptor, causing shape change, secretion and platelet aggregation.1 Also, COX-1 (599aa; 70 kDa) has cyclooxygenase and peroxidase activities and it is functionally active as a homodimer, with each COX-1 monomer consisting of four highly conserved domains: an N-terminal signal peptide, a dimerization domain, a membrane-binding domain (MBD) and a large C-terminal catalytic domain2 (Figure 1A). Irreversible COX-1 inhibition by aspirin is a widely established anti-platelet therapy in cardiovascular disease.3 Despite the physiological and clinical relevance of platelet COX-1, few patients with congenital COX-1 defect (Bleeding Disorder Platelet Type 12; OMIM: 605735) have been characterized.2 In the 1970s some patients with mild bleeding diathesis, impaired aggregation and blunted TXA2 synthesis were described, but with no genetic confirmation. To date, only a few cases with uncommon genetic variants in PTGS1, the gene encoding COX-1, have been reported, without detailed study of their associated platelet phenotype. A patient with severe bleeding carried the PTGS1 common single nucleotide variants (SNVs) c.22C>T [p.Arg8Trp] and c.50C>T (p.Pro17Leu)2 (gnomAD, minor allele frequency [MAF] = 0.0730 and 0.0588, respectively). Heterozygosity for the p.Pro17Leu variant also aggravated hemorrhage in a pedigree with hemophilia A.2 Another patient showing bleeding and reduced TXA2 synthesis was heterozygous for the rare PTGS1 variants c.337C>T (p.Arg113Cys) and c.1003G>A (p.Val481Ile) (MAF = 0.0000597 and 0.00718, respectively).2 Recently, the BRIDGE Consortium reported a pedigree with an autosomal recessive novel variant c.965G>C (p.Trp322Ser) that abrogated COX-1 expression resulting in aspirin-like platelet dysfunction.4 Here, we report a patient presenting with a lifelong mild bleeding tendency and platelet dysfunction, associated to heterozygosity for the novel PTGS1 variant c.428A>G (p.Asn143Ser). The distinguished feature of this rare SNV is that it disturbs one N-glycosylation sequon at the catalytic domain of COX-1 causing the expression of a dysfunctional hypo-glycosylated COX-1 protein with an apparent dominant-negative effect. The methodological details of this investigation are provided in supplemental material. The proband was a 13-year-old teen of Asiatic origin, adopted by a Spanish family, presenting with a lifelong moderate bleeding diathesis. There was bruising and petechiae, being more frequent after minor traumas; recurrent epistaxis sometimes associated with nonsteroidal anti-inflammatory drug (NSAIDs) intake; menorrhagia, once requiring tranexamic acid and desmopressin treatment; excessive bleeding after surgical procedures such as tonsillectomy(ISTH-BAT score 6). On repeated testing, she showed normal blood cell counts including platelet number and volume (Table S1 in Appendix S1) and no visible abnormalities in blood smears. Blood biochemical and coagulation parameters were within normal ranges. No clinical signs of relevant organ/tissue, immune or cognitive dysfunction were present. Detailed platelet phenotyping was performed that showed; (a) pathological PFA-100 closure time for the collagen/epinephrine cartridge (Table S1), (b) normal platelet receptor expression, reduced (50%) agonist-induced fibrinogen binding and impaired agonist-induced α-granule (10%–30%) and δ-granule (25%–50%) secretion (P-selectin and CD63 release, respectively) (Figure S1A–C in Appendix S1), (c) proband's platelets showed absent with AA-induced aggregation and normal with U46619, a stable TXA2 analog, indicating unaffected signaling downstream the TXA2 receptor (Figure 1B); platelet aggregation with other agonist was normal or slightly reduced (Figure S1D). Also, (d) markedly reduced platelet synthesis of","journal":"American Journal of Hematology","year":2020,"id":112059,"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":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9487,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":438398,"name":"Marilena Crescente","orcid":"0000-0003-3164-512X","position":1,"is_corresponding":false},{"id":530724,"name":"María Eugenia de la Morena‐Barrio","orcid":"0000-0001-7426-4947","position":2,"is_corresponding":false},{"id":438401,"name":"Melissa V. Chan","orcid":"0000-0003-2154-1386","position":3,"is_corresponding":false},{"id":530725,"name":"Elena Almarza","orcid":"0000-0002-4414-3455","position":4,"is_corresponding":false},{"id":530726,"name":"Nuria Revilla","orcid":"0000-0002-0995-1043","position":5,"is_corresponding":false},{"id":531327,"name":"Natalia Bohdan","orcid":null,"position":6,"is_corresponding":false},{"id":531328,"name":"Antonia Miñano","orcid":null,"position":7,"is_corresponding":false},{"id":530727,"name":"José Padilla","orcid":"0000-0003-1599-7870","position":8,"is_corresponding":false},{"id":438402,"name":"Harriet E. Allan","orcid":"0000-0002-2104-4972","position":9,"is_corresponding":false},{"id":439174,"name":"Tania Maffucci","orcid":null,"position":10,"is_corresponding":false},{"id":323202,"name":"Matthew L. Edin","orcid":"0000-0002-7042-500X","position":11,"is_corresponding":false},{"id":247404,"name":"Darryl C. Zeldin","orcid":"0000-0002-2087-7307","position":12,"is_corresponding":false},{"id":530728,"name":"Cristina Mesa-Núñez","orcid":"0000-0003-0581-0988","position":13,"is_corresponding":false},{"id":531329,"name":"Carlos Damián","orcid":null,"position":14,"is_corresponding":false},{"id":530729,"name":"Ana Marín‐Quilez","orcid":"0000-0002-2005-1919","position":15,"is_corresponding":false},{"id":530730,"name":"Rocí­o Benito","orcid":"0000-0001-9781-4198","position":16,"is_corresponding":false},{"id":530731,"name":"Irene Martínez‐Martínez","orcid":"0000-0002-1067-6464","position":17,"is_corresponding":false},{"id":530732,"name":"Nuria Bermejo","orcid":"0000-0002-9661-0318","position":18,"is_corresponding":false},{"id":531330,"name":"Ignacio Casas-Avilés","orcid":null,"position":19,"is_corresponding":false},{"id":530733,"name":"Agustín Rodríguez‐Alén","orcid":"0000-0003-3583-2977","position":20,"is_corresponding":false},{"id":530734,"name":"José Ramón González‐Porras","orcid":"0000-0003-3266-7996","position":21,"is_corresponding":false},{"id":530735,"name":"Jesús María Hernández‐Rivas","orcid":"0000-0002-9661-9371","position":22,"is_corresponding":false},{"id":530736,"name":"Vicente Vicente","orcid":"0000-0002-4278-3264","position":23,"is_corresponding":false},{"id":530737,"name":"Javier Corral","orcid":"0000-0003-0288-1107","position":24,"is_corresponding":false},{"id":530738,"name":"Marı́a Luisa Lozano","orcid":"0000-0003-3148-7037","position":25,"is_corresponding":false},{"id":438407,"name":"Timothy D. Warner","orcid":"0000-0003-3988-4408","position":26,"is_corresponding":false},{"id":530739,"name":"José María Bastida","orcid":"0000-0002-8007-3909","position":27,"is_corresponding":false},{"id":530740,"name":"José Rivera","orcid":"0000-0003-4225-6840","position":28,"is_corresponding":false},{"id":530723,"name":"Verónica Palma‐Barqueros","orcid":"0000-0002-5699-0053","position":0,"is_corresponding":true}],"reference_count":17,"raw_metadata":null,"created_at":"2026-07-18T23:13:09.353152Z","pmid":"33326144","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":[]}