Academic Journal
Novel variants in GALE cause syndromic macrothrombocytopenia by disrupting glycosylation and thrombopoiesis
| العنوان: | Novel variants in GALE cause syndromic macrothrombocytopenia by disrupting glycosylation and thrombopoiesis |
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| المؤلفون: | Marín-Quilez, Ana, Buduo, Christian A. Di, Díaz-Ajenjo, Lorena, Abbonante, Vittorio, Vuelta, Elena, Soprano, Paolo Maria, Miguel, Cristina, Santos-Mínguez, Sandra, Serramito-Gómez, Inmaculada, Ruiz-Sala, Pedro, Peñarrubia, María J., Pardal, Emilia, Hernández, Jesús M., González-Porras, José R., García-Tuñón, Ignacio, Benito, Rocío, Rivera, José, Balduini, Alessandra, Bastida, José María |
| المساهمون: | Instituto de Salud Carlos III, European Commission, Fundación Mutua Madrileña, Sociedad Española de Trombosis y Hemostasia, Fundación Castellano Leonesa de Hematología y Hemoterapia, Red Temática de Investigación Cooperativa en Cáncer (España), Centro de Investigación Biomédica en Red Cáncer (España), Junta de Castilla y León, Sociedad Española de Hematología y Hemoterapia, Universidad de Salamanca, European Research Council |
| بيانات النشر: | American Society of Hematology |
| سنة النشر: | 2023 |
| المجموعة: | Digital.CSIC (Consejo Superior de Investigaciones Científicas / Spanish National Research Council) |
| الوصف: | Glycosylation is recognized as a key process for proper megakaryopoiesis and platelet formation. The enzyme uridine diphosphate (UDP)-galactose-4-epimerase, encoded by GALE, is involved in galactose metabolism and protein glycosylation. Here, we studied 3 patients from 2 unrelated families who showed lifelong severe thrombocytopenia, bleeding diathesis, mental retardation, mitral valve prolapse, and jaundice. Whole-exome sequencing revealed 4 variants that affect GALE, 3 of those previously unreported (Pedigree A, p.Lys78ValfsX32 and p.Thr150Met; Pedigree B, p.Val128Met; and p.Leu223Pro). Platelet phenotype analysis showed giant and/or grey platelets, impaired platelet aggregation, and severely reduced alpha and dense granule secretion. Enzymatic activity of the UDP-galactose-4-epimerase enzyme was severely decreased in all patients. Immunoblotting of platelet lysates revealed reduced GALE protein levels, a significant decrease in N-acetyl-lactosamine (LacNAc), showing a hypoglycosylation pattern, reduced surface expression of gylcoprotein Ibα-IX-V (GPIbα-IX-V) complex and mature β1 integrin, and increased apoptosis. In vitro studies performed with patients-derived megakaryocytes showed normal ploidy and maturation but decreased proplatelet formation because of the impaired glycosylation of the GPIbα and β1 integrin, and reduced externalization to megakaryocyte and platelet membranes. Altered distribution of filamin A and actin and delocalization of the von Willebrand factor were also shown. Overall, this study expands our knowledge of GALE-related thrombocytopenia and emphasizes the critical role of GALE in the physiological glycosylation of key proteins involved in platelet production and function. ; This work was supported by grants from Instituto de Salud Carlos III (ISCIII) & Feder (PI17/01966, PI20/00926) and cofunded by European Union (ERDF/ESF, “Investing in your future”), Gerencia Regional de Salud (GRS2061/A/2019, GRS2135/A/2020, GRS2314/A/2021), Fundación Mutua Madrileña (FMM, AP172142019), ... |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | unknown |
| تدمد: | 0006-4971 |
| Relation: | #PLACEHOLDER_PARENT_METADATA_VALUE#; info:eu-repo/grantAgreement/EC/H2020/767309; Publisher's version; http://dx.doi.org/10.1182/blood.2022016995; Sí; e-issn: 1528-0020; Blood 141(4): 406-421 (2023); http://hdl.handle.net/10261/347825 |
| DOI: | 10.1182/blood.2022016995 |
| الاتاحة: | http://hdl.handle.net/10261/347825 https://doi.org/10.1182/blood.2022016995 |
| Rights: | open |
| رقم الانضمام: | edsbas.71F497BC |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 00064971 |
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| DOI: | 10.1182/blood.2022016995 |