Atp2b4, also known as plasma membrane calcium-transporting ATPase 4 (PMCA4), is a gene encoding a Ca2+ pump. It plays a crucial role in maintaining calcium homeostasis, which is essential for various cellular functions, such as cell signaling, muscle contraction, and neuronal activity. It is involved in pathways related to cell-volume regulation and is expressed in multiple tissues including red blood cells [2,3].

Genome-wide association studies have identified Atp2b4 as a severe malaria resistance gene. In a study with 154 individuals (79 controls and 75 mild malaria patients), nine SNPs in Atp2b4 were associated with mild malaria, and the homozygous genotypes for the major alleles increased the risk of mild malaria [1]. In another study, a regulatory region containing five Atp2B4 SNPs was associated with severe malaria in a Senegalese population, and deletion of this region in K562 cell line decreased Atp2b4 transcript and protein levels, and increased intracellular Ca2+ concentration [2]. An erythroid-specific enhancer of Atp2b4 was identified, and deletion of this enhancer in erythroid cells led to abnormally high intracellular calcium levels, suggesting its role in red blood cell hydration and malaria susceptibility [3].

In conclusion, Atp2b4 is essential for maintaining calcium homeostasis in cells. Studies, especially those using cell-based models with gene-editing techniques like CRISPR/Cas9, have revealed its significance in malaria resistance. These findings contribute to understanding the role of Atp2b4 in malaria-related biological processes and may potentially lead to new strategies for malaria treatment and prevention [1,2,3].