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In the human ATP2B4 gene, coding for the plasma membrane calcium pump PMCA4b, a minor haplotype results in the decreased expression of this membrane protein in erythroid cells. The presence of this haplotype and the consequently reduced PMCA4b expression have been suggested to affect red blood cell hydration and malaria susceptibility. By using dual-luciferase reporter assays, we have localized the erythroid-specific regulatory region within the haplotype of the ATP2B4 gene, containing predicted GATA1 binding sites that are affected by SNPs in the minor haplotype. Our results show that, in human erythroid cells, the regulation of ATP2B4 gene expression is significantly affected by GATA1 expression, and we document the role of specific SNPs involved in predicted GATA1 binding. Our findings provide a mechanistic explanation at the molecular level for the reduced erythroid-specific PMCA4b expression in carriers of ATP2B4 gene polymorphic variants.

Modulation of the Human Erythroid Plasma Membrane Calcium Pump (PMCA4b) Expression by Polymorphic Genetic Variants