Missense mutations in the ABVB6 transporter cause dominat familial pseudohyperkaliemia

Familial Pseudohyperkalemia (FP) is a dominant red cell trait characterized by increased serum [K1] inwhole blood stored at or below room temperature, without additional hematological abnormalities. Functionalgene mapping and sequencing analysis of the candidate genes within the 2q35–q36 critical intervalidentified—in 20 affected individuals among three multigenerational FP families—two novel heterozygousmissense mutations in the ABCB6 gene that cosegregated with disease phenotype. The two genomic substitutionsaltered two adjacent nucleotides within codon 375 of ABCB6, a porphyrin transporter that, inerythrocyte membranes, bears the Langereis blood group antigen system. The ABCB6 R375Q mutation didnot alter the levels of mRNA or protein, or protein localization in mature erythrocytes or erythroid precursorcells, but it is predicted to modestly alter protein structure. ABCB6 mRNA and protein levels increase duringin vitro erythroid differentiation of CD341 erythroid precursors and the erythroleukemia cell lines HELand K562. These data suggest that the two missense mutations in residue 375 of the ABCB6 polypeptidefound in affected individuals of families with chromosome 2-linked FP could contribute to the red cell K1leak characteristic of this condition.