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Volume 15
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Characterization of Novel Variants in P2YRY12, GP6 and TBXAS1 in Patients with Lifelong History of Bleeding

by
Ana Zamora-Cánovas
1,†,
Ana Marín-Quílez
1,†,
Lorena Díaz-Ajenjo
2,
Ana Sánchez-Fuentes
1,
Pedro Luis Gómez-González
1,
Marilena Crescente
3,
Nuria Fernández-Mosteirín
4,
José Padilla
1,
José Ramón González-Porras
2,5,
Rocío Benito
2,
María Luisa Lozano
1,
José María Bastida
2,5,‡ and
José Rivera Pozo
1,*,‡
1
Servicio de Hematología, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER-ISCIII, 30003 Murcia, Spain
2
Instituto de Investigación Biomédica de Salamanca (IBSAL), Centro de Investigación del Cáncer, IBMCC-CSIC, Universidad de Salamanca (USAL), 37007 Salamanca, Spain
3
Centre for Immunobiology, Faculty of Medicine and Dentistry, Blizard Institute, Queen Mary University of London, London E1 2AD, UK
4
Servicio de Hematología, Hospital Universitario Miguel Servet, 50009 Zaragoza, Spain
5
Departamento de Hematología, Complejo Asistencial Universitario de Salamanca (CAUSA), 37007 Salamanca, Spain
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
‡
On behalf of Grupo Español de Alteraciones Plaquetarias Congénitas (GEAPC). Share senior authorship.
Biomolecules 2025, 15(12), 1639; https://doi.org/10.3390/biom15121639
Submission received: 22 October 2025 / Revised: 14 November 2025 / Accepted: 16 November 2025 / Published: 21 November 2025
(This article belongs to the Section Molecular Biology)
Review Reports Versions Notes

Abstract

Inherited platelet function disorders (IPFDs) are rare diseases caused by defects in platelet surface receptors, enzymes, granules, or signaling proteins. In humans, GPVI and P2Y12 deficiency cause autosomal recessive bleeding disorders, while TBXAS1 deficiency is related to Ghosal hematodiaphyseal dysplasa, a rare autosomal recessive disorder characterized by increased long bone density and platelet dysfunction without bleeding. To date, at least 20 patients have been identified with molecular defects in P2RY12, 12 cases with molecular defects in GP6, and 34 cases with molecular defects in TBXAS1. Here, we report a novel nonsense and missense variants in P2RY12, a novel nonsense variant in GP6, and a novel missense variant in TBXAS1. These variants selectively affect the platelet reactivity to ADP and collagen/CRP, predisposing to bleeding. P2RY12 c.835 G>A [p.Val279Met] variant did not affect receptor expression whereas P2RY12 c.44delG [p.Ser15Ilefs*33] lead to decreased levels of the receptor in one of the patients. This was confirmed both by RT-qPCR and immunoblotting analysis. Decreased expression of both GPVI and FcRγ-chain was detected in patients carrying GPVI nonsense variant in heterozygosis. The deleterious effect of these variants was also confirmed in a transfected cell line model. TBXAS1 variant triggered decreased TxA2 production using a cell line model. These variants expand the genetic landscape of P2RY12, GPVI and TBXAS1 inherited deficiency.
Keywords: inherited platelet function disorders; IPFD; P2Y12 deficiency; GPVI deficiency; TBXAS1 deficiency; bleeding inherited platelet function disorders; IPFD; P2Y12 deficiency; GPVI deficiency; TBXAS1 deficiency; bleeding

Share and Cite

MDPI and ACS Style

Zamora-Cánovas, A.; Marín-Quílez, A.; Díaz-Ajenjo, L.; Sánchez-Fuentes, A.; Gómez-González, P.L.; Crescente, M.; Fernández-Mosteirín, N.; Padilla, J.; González-Porras, J.R.; Benito, R.; et al. Characterization of Novel Variants in P2YRY12, GP6 and TBXAS1 in Patients with Lifelong History of Bleeding. Biomolecules 2025, 15, 1639. https://doi.org/10.3390/biom15121639

AMA Style

Zamora-Cánovas A, Marín-Quílez A, Díaz-Ajenjo L, Sánchez-Fuentes A, Gómez-González PL, Crescente M, Fernández-Mosteirín N, Padilla J, González-Porras JR, Benito R, et al. Characterization of Novel Variants in P2YRY12, GP6 and TBXAS1 in Patients with Lifelong History of Bleeding. Biomolecules. 2025; 15(12):1639. https://doi.org/10.3390/biom15121639

Chicago/Turabian Style

Zamora-Cánovas, Ana, Ana Marín-Quílez, Lorena Díaz-Ajenjo, Ana Sánchez-Fuentes, Pedro Luis Gómez-González, Marilena Crescente, Nuria Fernández-Mosteirín, José Padilla, José Ramón González-Porras, Rocío Benito, and et al. 2025. "Characterization of Novel Variants in P2YRY12, GP6 and TBXAS1 in Patients with Lifelong History of Bleeding" Biomolecules 15, no. 12: 1639. https://doi.org/10.3390/biom15121639

APA Style

Zamora-Cánovas, A., Marín-Quílez, A., Díaz-Ajenjo, L., Sánchez-Fuentes, A., Gómez-González, P. L., Crescente, M., Fernández-Mosteirín, N., Padilla, J., González-Porras, J. R., Benito, R., Lozano, M. L., Bastida, J. M., & Rivera Pozo, J. (2025). Characterization of Novel Variants in P2YRY12, GP6 and TBXAS1 in Patients with Lifelong History of Bleeding. Biomolecules, 15(12), 1639. https://doi.org/10.3390/biom15121639

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