Platelet characteristics in patients with X-linked macrothrombocytopenia because of a novel GATA1mutation

Freson, Kathleen; Devriendt, Koenraad; Matthijs, Gert; Hoof, A Van; Vos, Rita De; Thys, Chantal; Minner, Kristien; Hoylaerts, Marc; Vermylen, Jozef; Geet, Christel Van

doi:10.1182/blood.v98.1.85

Cited by 226 publications

(212 citation statements)

References 29 publications

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“…12 Other amino-terminal zinc finger mutations affect cofactor binding and cause thrombocytopenia and dyserythropoiesis. [13][14][15][16] While we do not know that any of these cofactor binding face mutations result in a definitive gray platelet phenotype, these mutations do result in macrothrombocytopenia and/or ␣-granule deficiency. Therefore, we suggest that GATA1 mutations should be considered in seemingly sporadic, male cases of GPS.…”

Section: Resultsmentioning

confidence: 99%

X-linked gray platelet syndrome due to a GATA1 Arg216Gln mutation

Tubman

Levine

Campagna

et al. 2007

Blood

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We identified a family with gray platelet syndrome (GPS) segregating as a sexlinked trait. Affected males had a mild bleeding disorder, thrombocytopenia, and large agranular platelets characteristic of GPS, while obligate carrier females were asymptomatic but had dimorphic platelets on peripheral smear. Associated findings included mild erythrocyte abnormalities in affected males. Linkage analysis revealed a 63 cM region on the X chromosome between markers G10578 and DXS6797, which segregated with the platelet phenotype and included the GATA1 gene. Sequencing of GATA1 revealed a G-to-A mutation at position 759 corresponding to amino acid change Arg216Gln. This mutation was previously described as a cause of X-linked thrombocytopenia with thalassemia (XLTT) but not of gray platelet syndrome. Our findings suggest that XLTT is within a spectrum of disorders constituting the gray platelet syndrome, and we propose that GATA1 is an upstream regulator of the genes required for platelet ␣-granule biogenesis. IntroductionGray platelet syndrome (GPS) is a rare, mild bleeding diathesis characterized by large dysfunctional, agranular platelets that appear gray on Wright-stained peripheral blood smears. Patients exhibit bruising and mucocutaneous bleeding out of proportion to their mild to moderate thrombocytopenia. Since the first description in 1971, 1 many sporadic cases as well as a few autosomal dominant 2 and recessive 3 pedigrees, totaling approximately 60 cases, have been reported. While GPS has been described biochemically and pathologically, no mutation has been associated with this disorder. This report describes a new GPS pedigree wherein the disorder segregates with a missense mutation in GATA1. Patients, materials, and methodsA healthy 1-year-old female presented for evaluation of a family history of thrombocytopenia. Her father and paternal uncle, both with lifelong histories of bruising and bleeding, had been diagnosed with GPS previously; in fact, her uncle has been described previously ( Figure 1A). 4 The family history was notable for multiple male relatives in the paternal lineage with bleeding symptoms ( Figure 1A). The proband had no bleeding history and had a normal physical examination and complete blood count (CBC), including a platelet count of 382 ϫ 10 9 /L (382 000/L). Review of her peripheral blood smear revealed 2 distinct populations of platelets: one normal appearing; the other large, agranular, and pale ( Figure 1B).Subjects provided written, informed consent in accordance with Children's Hospital Committee of Clinical Investigation and the Declaration of Helsinki. May-Grünwald-Giemsa (Sigma, St. Louis, MO)-stained peripheral blood smears were photographed using a Nikon Eclipse E600 microscope equipped with a 100ϫ/0.30 numerical aperture oil immersion lens and an RT Slider SPOT 2.3.1 camera (Diagnostic Instruments, Sterling Heights, MI) using SPOT Advanced software (version 3.5.9). DNA was extracted from peripheral blood leukocytes using the Puregene DNA Purification Kit (Gentra, Minneapolis...

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Section: Resultsmentioning

confidence: 99%

X-linked gray platelet syndrome due to a GATA1 Arg216Gln mutation

Tubman

Levine

Campagna

et al. 2007

Blood

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“…Vertebrate GATA-1 and Runx1 are coexpressed and have overlapping functions during hematopoiesis, including megakaryopoiesis (15)(16)(17)(18)(19)(20)(21)(22). In addition, in vitro studies have suggested that the GATA-1:Runx1 complex directs megakaryocyte differentiation (22).…”

Section: Srp and Lz Synergistically Activate The Crystal Cell Programmentioning

confidence: 99%

Combinatorial interactions of Serpent, Lozenge, and U-shaped regulate crystal cell lineage commitment during Drosophila hematopoiesis

Fossett

Hyman

Gajewski

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

120

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The GATA factor Serpent (Srp) is required for hemocyte precursor formation during Drosophila hematopoiesis. These blood cell progenitors give rise to two distinct lineages within the developing embryo. Lozenge, a Runx protein homologue, and Glial cells missing-1 and -2 are essential for crystal cell and plasmatocyte production, respectively. In contrast U-shaped, a Friend of GATA class factor, antagonizes crystal cell formation. Here we show that Srp, Lozenge, and U-shaped interact in different combinations to regulate crystal cell lineage commitment. Coexpression of Srp and Lozenge synergistically activated the crystal cell program in both embryonic and larval stages. Furthermore, expression of Lozenge and SrpNC, a Srp isoform with N-and C-terminal zinc fingers, inhibited u-shaped expression, indicating that crystal cell activation coincided with the down-regulation of this repressor-encoding gene. In contrast, whereas U-shaped and SrpNC together blocked crystal cell production, coexpression of U-shaped with noninteracting Srp proteins failed to prevent overproduction of this hemocyte population. Such results indicated that U-shaped and SrpNC must interact to block crystal cell production. Taken together, these studies show that the specialized SrpNC isoform plays a pivotal role during crystal cell lineage commitment, acting as an activator or repressor depending on the availability of specific transcriptional coregulators. These findings provide definitive proof of the combinatorial regulation of hematopoiesis in Drosophila and an in vivo demonstration of GATA and Runx functional interaction in a blood cell commitment program.

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“…For instance, somatic mutations in the GATA1 gene, which result in the production of GATA1-⌬NT (or GATA1s), are a prerequisite for the onset of transient myeloproliferative disorder (TMD) and subsequent acute megakaryoblastic leukemia (AMkL) in Down syndrome patients (44). Similarly, GATA1 mutations in the N-finger domain were found in multiple cases with familial anemia and thrombocytopenia (45)(46)(47)(48). In the latter cases, the association potential of GATA1 with either FOG1 or GATAbox DNA was attenuated, indicating that the N-finger domain is important for the GATA1 activity.…”

Section: Discussionmentioning

confidence: 99%

N- and C-terminal Transactivation Domains of GATA1 Protein Coordinate Hematopoietic Program

Kaneko

Kobayashi

Yamamoto

et al. 2012

Journal of Biological Chemistry

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Background:The N-terminal transactivation domain (N-TAD) is requisite for GATA1 function in vivo. Results: The C-terminal region of GATA1 works as TAD, and fetal hematopoiesis is perturbed in the GATA1-deficient mice rescued with GATA1 lacking C-terminal TAD activity. Conclusion: GATA1 has two TADs, which differentially work. Significance: The complex nature of molecular mechanisms is underlying how GATA1 works for the maintenance of hematopoietic homeostasis.

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Platelet characteristics in patients with X-linked macrothrombocytopenia because of a novel GATA1mutation

Cited by 226 publications

References 29 publications

X-linked gray platelet syndrome due to a GATA1 Arg216Gln mutation

X-linked gray platelet syndrome due to a GATA1 Arg216Gln mutation

Combinatorial interactions of Serpent, Lozenge, and U-shaped regulate crystal cell lineage commitment during Drosophila hematopoiesis

N- and C-terminal Transactivation Domains of GATA1 Protein Coordinate Hematopoietic Program

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