Novel GATA1 Variant Causing a Bleeding Phenotype Associated with Combined Platelet α-/δ-Storage Pool Deficiency and Mild Dyserythropoiesis Modified by a SLC4A1 Variant
Open Access
- 29 September 2022
- Vol. 11 (19), 3071
- https://doi.org/10.3390/cells11193071
Abstract
Germline defects in the transcription factor GATA1 are known to cause dyserythropoiesis with(out) anemia and variable abnormalities in platelet count and function. However, damaging variants closely located to the C-terminal zinc finger domain of GATA1 are nearly unknown. In this study, a 36-year-old male index patient and his 4-year-old daughter suffered from moderate mucocutaneous bleeding diathesis since birth. Whole exome sequencing detected a novel hemizygous GATA1 missense variant, c.886A>C p.T296P, located between the C-terminal zinc finger and the nuclear localization sequence with non-random X-chromosome inactivation in the heterozygous daughter. Blood smears from both patients demonstrated large platelet fractions and moderate thrombocytopenia in the index. Flow cytometry and electron microscopy analysis supported a combined α-/δ (AN-subtype)-storage pool deficiency as cause for impaired agonist-induced platelet aggregation (light transmission aggregometry) and granule exocytosis (flow cytometry). The absence of BCAM in the index (Lu(a-b-)) and its low expression in the daughter (Lu(a-b+)) confirmed a less obvious effect of defective GATA1 also on erythrocytes. Borderline anemia, elevated HbF levels, and differential transcription of GATA1-regulated genes indicated mild dyserythropoiesis in both patients. Furthermore, a mild SLC4A1 defect associated with a heterozygous SLC4A1 c.2210C>T p.A737V variant maternally transmitted in the daughter may modify the disease to mild spherocytosis and hemolysis.Keywords
Funding Information
- German Federal Ministry of Education and Research (BMBF 01EO1503)
This publication has 54 references indexed in Scilit:
- Extracellular protein disulfide isomerase regulates feedback activation of platelet thrombin generation via modulation of coagulation factor bindingJournal of Thrombosis and Haemostasis, 2011
- Role of MRP4 (ABCC4) in Platelet Adenine Nucleotide-Storage: Evidence from Patients with Delta-Storage Pool DeficienciesThe American Journal of Pathology, 2010
- A Novel Approach to CFTR Mutation Testing by Pyrosequencing-Based Assay Panels Adapted to EthnicitiesClinical Chemistry, 2009
- Platelet structural pathology in a patient with the X-linked GATA-1, R216Q mutationPlatelets, 2009
- Response: X-chromosome inactivation and autoimmunityBlood, 2007
- Evaluation of a New Pooling Strategy Based on Leukocyte Count for Rapid Quantification of Allele FrequenciesClinical Chemistry, 2007
- Platelet pathology in carriers of the X-linked GATA-1 macrothrombocytopeniaPlatelets, 2007
- Congenital erythropoietic porphyria due to a mutation in GATA1: the first trans-acting mutation causative for a human porphyriaBlood, 2006
- Selective impairment of platelet activation to collagen in the absence of GATA1Blood, 2005
- Platelets in patients with acute ischemic stroke are exhausted and refractory to thrombin, due to cleavage of the seven-transmembrane thrombin receptor (PAR-1)Thrombosis and Haemostasis, 2004