2026-09-14T14:17:41Zhttps://gredos.usal.es/oai/request

oai:gredos.usal.es:10366/1717182026-06-04T00:02:06Zcom_10366_132632com_10366_4512com_10366_3823col_10366_132633

Palma-Barqueros, Verónica Loredana, Bury Kunishima, Shinji Lozano, María Luisa Rodríguez-Alen, Augustín Revilla, Nuria Bohdan, Natalia Padilla, José Fernández-Pérez, María P de la Morena-Barrio, María Eugenia Marín-Quilez, Ana Benito Sánchez, Rocío López-Fernández, María F Marcellini, Shally Zamora-Cánovas, Ana Vicente, Vicente Martínez, Constantino Gresele, Paolo Bastida Bermejo, José María Rivera, José 2026-06-03T11:59:54Z 2026-06-03T11:59:54Z 2021 Palma-Barqueros, V., Bury, L., Kunishima, S., Lozano, M. L., Rodríguez-Alen, A., Revilla, N., ... & Rivera, J. (2021). Expanding the genetic spectrum of TUBB1-related thrombocytopenia. Blood advances, 5(24), 5453-5467. http://hdl.handle.net/10366/171718 10.1182/BLOODADVANCES.2020004057 36920438 2473-9537 [EN]β1-Tubulin plays a major role in proplatelet formation and platelet shape maintenance, and pathogenic variants in TUBB1 lead to thrombocytopenia and platelet anisocytosis (TUBB1-RT). To date, the reported number of pedigrees with TUBB1-RT and of rare TUBB1 variants with experimental demonstration of pathogenicity is limited. Here, we report 9 unrelated families presenting with thrombocytopenia carrying 6 β1-tubulin variants, p.Cys12LeufsTer12, p.Thr107Pro, p.Gln423*, p.Arg359Trp, p.Gly109Glu, and p.Gly269Asp, the last of which novel. Segregation studies showed incomplete penetrance of these variants for platelet traits. Indeed, most carriers showed macrothrombocytopenia, some only increased platelet size, and a minority had no abnormalities. Moreover, only homozygous carriers of the p.Gly109Glu variant displayed macrothrombocytopenia, highlighting the importance of allele burden in the phenotypic expression of TUBB1-RT. The p.Arg359Trp, p.Gly269Asp, and p.Gly109Glu variants deranged β1-tubulin incorporation into the microtubular marginal ring in platelets but had a negligible effect on platelet activation, secretion, or spreading, suggesting that β1-tubulin is dispensable for these processes. Transfection of TUBB1 missense variants in CHO cells altered β1-tubulin incorporation into the microtubular network. In addition, TUBB1 variants markedly impaired proplatelet formation from peripheral blood CD34+ cell-derived megakaryocytes. Our study, using in vitro modeling, molecular characterization, and clinical investigations provides a deeper insight into the pathogenicity of rare TUBB1 variants. These novel data expand the genetic spectrum of TUBB1-RT and highlight a remarkable heterogeneity in its clinical presentation, indicating that allelic burden or combination with other genetic or environmental factors modulate the phenotypic impact of rare TUBB1 variants. eng http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess Attribution 4.0 International TUBB1-related thrombocytopenia Platelets Thrombopoiesis Expanding the genetic spectrum of TUBB1-related thrombocytopenia info:eu-repo/semantics/article