A novel genetic variant in PTGS1 affects N-glycosylation of cyclooxygenase-1 causing a dominant-negative effect on platelet function and bleeding diathesis
- Palma-Barqueros, Verónica
- Crescente, Marilena
- Morena, María Eugenia de la
- Chan, Melissa V.
- Almarza, Elena
- Revilla, Nuria
- Bohdan, Natalia
- Miñano, Antonia
- Padilla, Jose
- Allan, Harriet E.
- Maffucci, Tania
- Edin, Matthew L.
- Zeldin, Darryl C.
- Mesa-Nuñez, Cristina
- Damian, Carlos
- Marín-Quilez, Ana
- Benito, Rocío
- Martínez-Martínez, Irene
- Bermejo, Nuria
- Casas-Aviles, Ignacio
- Rodriguez-Alén, Agustín
- González-Porras, José R.
- Hernández, Jesús M.
- Vicente, Vicente
- Corral, J.
- Lozano, María L.
- Warner, Timothy D.
- Bastida, José María
- Rivera, José
DOIAbstract
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.Funda...
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