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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...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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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. |
format | Online Article Text |
id | pubmed-9600848 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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