title: Missense mutations in the ABCB6 transporter cause dominant familial pseudohyperkalemia.
abstract: Familial Pseudohyperkalemia (FP) is a dominant red cell trait characterized by increased serum [K(+)] in whole blood stored at or below room temperature, without additional hematological abnormalities. Functional gene mapping and sequencing analysis of the candidate genes within the 2q35-q36 critical interval identified-in 20 affected individuals among three multigenerational FP families-two novel heterozygous missense mutations in the ABCB6 gene that cosegregated with disease phenotype. The two genomic substitutions altered two adjacent nucleotides within codon 375 of ABCB6, a porphyrin transporter that, in erythrocyte membranes, bears the Langereis blood group antigen system. The ABCB6 R375Q mutation did not alter the levels of mRNA or protein, or protein localization in mature erythrocytes or erythroid precursor cells, but it is predicted to modestly alter protein structure. ABCB6 mRNA and protein levels increase during in vitro erythroid differentiation of CD34(+) erythroid precursors and the erythroleukemia cell lines HEL and K562. These data suggest that the two missense mutations in residue 375 of the ABCB6 polypeptide found in affected individuals of families with chromosome 2-linked FP could contribute to the red cell K(+) leak characteristic of this condition.
authors.affiliation: CEINGE, Biotecnologie Avanzate, Naples, Italy.
authors.forename: Immacolata
authors.initials: I
authors.lastname: Andolfo
authors.forename: Seth L
authors.initials: SL
authors.lastname: Alper
authors.forename: Jean
authors.initials: J
authors.lastname: Delaunay
authors.forename: Carla
authors.initials: C
authors.lastname: Auriemma
authors.forename: Roberta
authors.initials: R
authors.lastname: Russo
authors.forename: Roberta
authors.initials: R
authors.lastname: Asci
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Esposito
authors.forename: Alok K
authors.initials: AK
authors.lastname: Sharma
authors.forename: Boris E
authors.initials: BE
authors.lastname: Shmukler
authors.forename: Carlo
authors.initials: C
authors.lastname: Brugnara
authors.forename: Lucia
authors.initials: L
authors.lastname: De Franceschi
authors.forename: Achille
authors.initials: A
authors.lastname: Iolascon
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D019943:Amino Acid Substitution; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D003062:Codon; D015672:Erythroid Precursor Cells; D005260:Female; D006801:Humans; D006947:Hyperkalemia / Q000097:blood / Q000151:congenital* / Q000235:genetics; D020014:K562 Cells; D008661:Metabolism, Inborn Errors / Q000097:blood / Q000235:genetics*; D020125:Mutation, Missense; D011188:Potassium / Q000097:blood
chemical_list: C107991:ABCB6 protein, human; D018528:ATP-Binding Cassette Transporters; D003062:Codon; D011188:Potassium