Novel GATA1 Variant Causing a Bleeding Phenotype Associated with Combined Platelet α-/δ-Storage Pool Deficiency and Mild Dyserythropoiesis Modified by a SLC4A1 Variant.
Kerstin JurkAnke AdenaeuerStefanie SollfrankKathrin GroßFriederike HäuserAndreas CzwalinnaJosef ErkelNele FritschDana MarandiucMartin SchallerKarl J LacknerHeidi RossmannFrauke BergmannPublished in: Cells (2022)
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.
Keyphrases
- transcription factor
- flow cytometry
- end stage renal disease
- chronic kidney disease
- ejection fraction
- newly diagnosed
- dna binding
- peritoneal dialysis
- high intensity
- prognostic factors
- atrial fibrillation
- gene expression
- copy number
- dna methylation
- dna damage
- long non coding rna
- pregnant women
- genome wide
- high glucose
- iron deficiency
- patient reported
- drug induced