GATA1 pathogenic variants disrupt MYH10 silencing during megakaryopoiesis

Saultier, Paul; Cabantous, Stéphanie; Pucéat, Michel; Peiretti, Franck; Bigot, Timothée; Bordet, Jean‐Claude; Canault, Matthias; Agthoven, Johannes van; Loosveld, Marie; Payet-Bornet, Dominique; Potier, Delphine; Falaise, Céline; Bernot, Denis; Morange, Pierre‐Emmanuel; Alessi, Marie‐Christine; Poggi, Marjorie

doi:10.1111/jth.15412

Cited by 7 publications

(6 citation statements)

References 48 publications

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“…The novelty is the identification of a new GATA1 variant in the C-terminal ZF of GATA1 described in unrelated German (pedigree B) and Spanish patients (pedigree C), independently. The C-ZF domain has been shown to be essential to induce megakaryocytic differentiation [ 53 , 54 ]. The hemizygous males (B I.1 and C I.1) presented with mucocutaneous bleeding and a platelet function disorder but without obvious thrombocytopenia, although patient C I.1 showed variable platelet counts ranging from 123 to 215 × 10 9 /L throughout the years.…”

Section: Discussionmentioning

confidence: 99%

“…More recently, another novel GATA1 variant within the C-terminal zinc finger domain, p.Leu268Met (L268M), has been described in two brothers who suffered from prolonged bleeding and pronounced mucocutaneous hemorrhages. These patients showed severe platelet dysfunction and displayed a significant reduction in α- and δ-granules [ 53 ]. Postoperative bleeding after minor surgeries was prevented by the administration of platelet concentrates.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, patient B I.1′s hemoglobin value was within the lower normal range and erythrocytes were macrocytic, suggesting an implication of the p.H289Y variant in erythropoiesis. Similarly, patients with the p.L268M variant show no anemia but show progressively enlarged erythrocytes, possibly prodromal of a bone marrow failure [ 53 ]. Further studies and follow-up of patients are needed to monitor the impact of C-ZF variants on megakaryopoiesis and the red cell line.…”

Section: Discussionmentioning

confidence: 99%

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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

Bastida

Malvestiti

Boeckelmann

et al. 2022

Cells

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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

Bastida

Malvestiti

Boeckelmann

et al. 2022

Cells

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“…Additionally, cell division is attenuated in the megakaryocytic progenitor G1ME cells that overexpress GATA1. A recent report further shows that impaired MYH10 silencing causes GATA1-related polyploidization defect during megakaryocyte differentiation ( 44 ).…”

Section: Transcription Factors In Platelet Productionmentioning

confidence: 94%

Transcription factors in megakaryocytes and platelets

et al. 2023

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Transcription factors bind promoter or regulatory sequences of a gene to regulate its rate of transcription. However, they are also detected in anucleated platelets. The transcription factors RUNX1, GATA1, STAT3, NFκB, and PPAR have been widely reported to play key roles in the pathophysiology of platelet hyper-reactivity, thrombosis, and atherosclerosis. These non-transcriptional activities are independent of gene transcription or protein synthesis but their underlying mechanisms of action remain poorly defined. Genetic and acquired defects in these transcription factors are associated with the production of platelet microvesicles that are known to initiate and propagate coagulation and to promote thrombosis. In this review, we summarize recent developments in the study of transcription factors in platelet generation, reactivity, and production of microvesicles, with a focus on non-transcriptional activities of selected transcription factors.

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“…Of note, several substitutions in the C-finger and downstream region have also been identified (Figure 2A) and have intriguing pathological impacts (38,56,(58)(59)(60)(61)(62). Affected males carrying either L268M, H289Y or T296P mutations suffer from bleeding disorders caused by platelet dysfunction, while platelet numbers indicate borderline or mild-to-moderate thrombocytopenia.…”

Section: Gata1 Mutations With Qualitative Protein Defects and Diseasesmentioning

confidence: 99%

Recent progress in analyses of GATA1 in hematopoietic disorders: a mini-review

Shimizu

Yamamoto

2023

Front. Hematol.

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GATA1 is an essential master regulator of erythropoiesis and megakaryopoiesis. Accumulating lines of evidence have shown that dynamic changes in GATA1 gene expression levels during erythropoiesis are crucial for proper erythroid differentiation. Since GATA1 is an X-chromosome gene, GATA1 knockout leads to embryonic lethal dyserythropoiesis in male mice, while heterozygous female mice can survive. In the past decade, it has become clear that germline GATA1 gene mutations leading to structural changes in the GATA1 protein are involved in congenital dyserythropoiesis in males. In contrast, decreased GATA1 expression levels, which cause embryonic lethal dyserythropoiesis in male mice, increase the risk of erythroleukemia development in female mice, while female GATA1-knockout mice do not show substantial phenotypic alterations in erythroid or megakaryocyte lineages. In this review, we summarize the recent progress in elucidating the roles of GATA1 in normal and pathogenetic erythropoiesis and discuss the possible mechanisms of pathogenesis of dyserythropoiesis and erythroleukemia.

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GATA1 pathogenic variants disrupt MYH10 silencing during megakaryopoiesis

Cited by 7 publications

References 48 publications

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

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

Transcription factors in megakaryocytes and platelets

Recent progress in analyses of GATA1 in hematopoietic disorders: a mini-review

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