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A Novel GATA1 Variant in the C-Terminal Zinc Finger Compared with the Platelet Phenotype of Patients with A Likely Pathogenic Variant in the N-Terminal Zinc Finger

The GATA1 transcription factor is essential for normal erythropoiesis and megakaryocytic differentiation. Germline GATA1 pathogenic variants in the N-terminal zinc finger (N-ZF) are typically associated with X-linked thrombocytopenia, platelet dysfunction, and dyserythropoietic anemia. A few variant...

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Autores principales: Bastida, José M., Malvestiti, Stefano, Boeckelmann, Doris, Palma-Barqueros, Verónica, Wolter, Mira, Lozano, María L., Glonnegger, Hannah, Benito, Rocío, Zaninetti, Carlo, Sobotta, Felix, Schilling, Freimut H., Morgan, Neil V., Freson, Kathleen, Rivera, José, Zieger, Barbara
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9600848/
https://www.ncbi.nlm.nih.gov/pubmed/36291092
http://dx.doi.org/10.3390/cells11203223
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author Bastida, José M.
Malvestiti, Stefano
Boeckelmann, Doris
Palma-Barqueros, Verónica
Wolter, Mira
Lozano, María L.
Glonnegger, Hannah
Benito, Rocío
Zaninetti, Carlo
Sobotta, Felix
Schilling, Freimut H.
Morgan, Neil V.
Freson, Kathleen
Rivera, José
Zieger, Barbara
author_facet Bastida, José M.
Malvestiti, Stefano
Boeckelmann, Doris
Palma-Barqueros, Verónica
Wolter, Mira
Lozano, María L.
Glonnegger, Hannah
Benito, Rocío
Zaninetti, Carlo
Sobotta, Felix
Schilling, Freimut H.
Morgan, Neil V.
Freson, Kathleen
Rivera, José
Zieger, Barbara
author_sort Bastida, José M.
collection PubMed
description The GATA1 transcription factor is essential for normal erythropoiesis and megakaryocytic differentiation. Germline GATA1 pathogenic variants in the N-terminal zinc finger (N-ZF) are typically associated with X-linked thrombocytopenia, platelet dysfunction, and dyserythropoietic anemia. A few variants in the C-terminal ZF (C-ZF) domain are described with normal platelet count but altered platelet function as the main characteristic. Independently performed molecular genetic analysis identified a novel hemizygous variant (c.865C>T, p.H289Y) in the C-ZF region of GATA1 in a German patient and in a Spanish patient. We characterized the bleeding and platelet phenotype of these patients and compared these findings with the parameters of two German siblings carrying the likely pathogenic variant p.D218N in the GATA1 N-ZF domain. The main difference was profound thrombocytopenia in the brothers carrying the p.D218N variant compared to a normal platelet count in patients carrying the p.H289Y variant; only the Spanish patient occasionally developed mild thrombocytopenia. A functional platelet defect affecting αIIbβ3 integrin activation and α-granule secretion was present in all patients. Additionally, mild anemia, anisocytosis, and poikilocytosis were observed in the patients with the C-ZF variant. Our data support the concept that GATA1 variants located in the different ZF regions can lead to clinically diverse manifestations.
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spelling pubmed-96008482022-10-27 A Novel GATA1 Variant in the C-Terminal Zinc Finger Compared with the Platelet Phenotype of Patients with A Likely Pathogenic Variant in the N-Terminal Zinc Finger Bastida, José M. Malvestiti, Stefano Boeckelmann, Doris Palma-Barqueros, Verónica Wolter, Mira Lozano, María L. Glonnegger, Hannah Benito, Rocío Zaninetti, Carlo Sobotta, Felix Schilling, Freimut H. Morgan, Neil V. Freson, Kathleen Rivera, José Zieger, Barbara Cells Article The GATA1 transcription factor is essential for normal erythropoiesis and megakaryocytic differentiation. Germline GATA1 pathogenic variants in the N-terminal zinc finger (N-ZF) are typically associated with X-linked thrombocytopenia, platelet dysfunction, and dyserythropoietic anemia. A few variants in the C-terminal ZF (C-ZF) domain are described with normal platelet count but altered platelet function as the main characteristic. Independently performed molecular genetic analysis identified a novel hemizygous variant (c.865C>T, p.H289Y) in the C-ZF region of GATA1 in a German patient and in a Spanish patient. We characterized the bleeding and platelet phenotype of these patients and compared these findings with the parameters of two German siblings carrying the likely pathogenic variant p.D218N in the GATA1 N-ZF domain. The main difference was profound thrombocytopenia in the brothers carrying the p.D218N variant compared to a normal platelet count in patients carrying the p.H289Y variant; only the Spanish patient occasionally developed mild thrombocytopenia. A functional platelet defect affecting αIIbβ3 integrin activation and α-granule secretion was present in all patients. Additionally, mild anemia, anisocytosis, and poikilocytosis were observed in the patients with the C-ZF variant. Our data support the concept that GATA1 variants located in the different ZF regions can lead to clinically diverse manifestations. MDPI 2022-10-14 /pmc/articles/PMC9600848/ /pubmed/36291092 http://dx.doi.org/10.3390/cells11203223 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Bastida, José M.
Malvestiti, Stefano
Boeckelmann, Doris
Palma-Barqueros, Verónica
Wolter, Mira
Lozano, María L.
Glonnegger, Hannah
Benito, Rocío
Zaninetti, Carlo
Sobotta, Felix
Schilling, Freimut H.
Morgan, Neil V.
Freson, Kathleen
Rivera, José
Zieger, Barbara
A Novel GATA1 Variant in the C-Terminal Zinc Finger Compared with the Platelet Phenotype of Patients with A Likely Pathogenic Variant in the N-Terminal Zinc Finger
title A Novel GATA1 Variant in the C-Terminal Zinc Finger Compared with the Platelet Phenotype of Patients with A Likely Pathogenic Variant in the N-Terminal Zinc Finger
title_full A Novel GATA1 Variant in the C-Terminal Zinc Finger Compared with the Platelet Phenotype of Patients with A Likely Pathogenic Variant in the N-Terminal Zinc Finger
title_fullStr A Novel GATA1 Variant in the C-Terminal Zinc Finger Compared with the Platelet Phenotype of Patients with A Likely Pathogenic Variant in the N-Terminal Zinc Finger
title_full_unstemmed A Novel GATA1 Variant in the C-Terminal Zinc Finger Compared with the Platelet Phenotype of Patients with A Likely Pathogenic Variant in the N-Terminal Zinc Finger
title_short A Novel GATA1 Variant in the C-Terminal Zinc Finger Compared with the Platelet Phenotype of Patients with A Likely Pathogenic Variant in the N-Terminal Zinc Finger
title_sort novel gata1 variant in the c-terminal zinc finger compared with the platelet phenotype of patients with a likely pathogenic variant in the n-terminal zinc finger
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9600848/
https://www.ncbi.nlm.nih.gov/pubmed/36291092
http://dx.doi.org/10.3390/cells11203223
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