title: Decreased calcium pump expression in human erythrocytes is connected to a minor haplotype in the ATP2B4 gene.
abstract: Plasma membrane Ca2+-ATPases are key calcium exporter proteins in most tissues, and PMCA4b is the main calcium transporter in the human red blood cells (RBCs). In order to assess the expression level of PMCA4b, we have developed a flow cytometry and specific antibody binding method to quantitatively detect this protein in the erythrocyte membrane. Interestingly, we found several healthy volunteers showing significantly reduced expression of RBC-PMCA4b. Western blot analysis of isolated RBC membranes confirmed this observation, and indicated that there are no compensatory alterations in other PMCA isoforms. In addition, reduced PMCA4b levels correlated with a lower calcium extrusion capacity in these erythrocytes. When exploring the potential genetic background of the reduced PMCA4b levels, we found no missense mutations in the ATP2B4 coding regions, while a formerly unrecognized minor haplotype in the predicted second promoter region closely correlated with lower erythrocyte PMCA4b protein levels. In recent GWA studies, SNPs in this ATP2B4 haplotype have been linked to reduced mean corpuscular hemoglobin concentrations (MCHC), and to protection against malaria infection. Our data suggest that an altered regulation of gene expression is responsible for the reduced RBC-PMCA4b levels that is probably linked to the development of human disease-related phenotypes.
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudosok krt. 2, Budapest, 1117, Hungary.
authors.forename: Boglárka
authors.initials: B
authors.lastname: Zámbó
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudosok krt. 2, Budapest, 1117, Hungary.
authors.forename: György
authors.initials: G
authors.lastname: Várady
authors.affiliation: 2nd Department of Pathology, Faculty of Medicine, Semmelweis University, Ulloi ut 26., Budapest, 1085, Hungary.
authors.forename: Rita
authors.initials: R
authors.lastname: Padányi
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudosok krt. 2, Budapest, 1117, Hungary.
authors.forename: Edit
authors.initials: E
authors.lastname: Szabó
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudosok krt. 2, Budapest, 1117, Hungary.
authors.forename: Adrienn
authors.initials: A
authors.lastname: Németh
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudosok krt. 2, Budapest, 1117, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Langó
authors.affiliation: 2nd Department of Pathology, Faculty of Medicine, Semmelweis University, Ulloi ut 26., Budapest, 1085, Hungary; Molecular Oncology Research Group of the Hungarian Academy of Sciences and Semmelweis University, Ulloi ut 26., Budapest, 1085, Hungary.
authors.forename: Ágnes
authors.initials: Á
authors.lastname: Enyedi
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudosok krt. 2, Budapest, 1117, Hungary; MTA-SE Molecular Biophysics Research Group, Department of Biophysics and Radiation Biology, Semmelweis University, Tuzolto u. 37-43., Budapest, 1094, Hungary. Electronic address: sarkadi@biomembrane.hu.
authors.forename: Balázs
authors.initials: B
authors.lastname: Sarkadi
mesh_terms: D004912:Erythrocytes / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006239:Haplotypes; D006454:Hemoglobins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000096:biosynthesis / Q000235:genetics; D020641:Polymorphism, Single Nucleotide
chemical_list: D006454:Hemoglobins; C507517:ATP2B4 protein, human; D053499:Plasma Membrane Calcium-Transporting ATPases
keywords: ATP2B4; Ca(2+); Erythrocytes; Haplotype; PMCA4b; Promoter