title: Monovalent cation leaks in human red cells caused by single amino-acid substitutions in the transport domain of the band 3 chloride-bicarbonate exchanger, AE1.
abstract: We identified 11 human pedigrees with dominantly inherited hemolytic anemias in both the hereditary stomatocytosis and spherocytosis classes. Affected individuals in these families had an increase in membrane permeability to Na and K that is particularly marked at 0 degrees C. We found that disease in these pedigrees was associated with a series of single amino-acid substitutions in the intramembrane domain of the erythrocyte band 3 anion exchanger, AE1. Anion movements were reduced in the abnormal red cells. The 'leak' cation fluxes were inhibited by SITS, dipyridamole and NS1652, chemically diverse inhibitors of band 3. Expression of the mutated genes in Xenopus laevis oocytes induced abnormal Na and K fluxes in the oocytes, and the induced Cl transport was low. These data are consistent with the suggestion that the substitutions convert the protein from an anion exchanger into an unregulated cation channel.
authors.affiliation: Bristol Institute for Transfusion Sciences, National Blood Service, Southmead, Bristol BS10 5ND, UK.
authors.forename: Lesley J
authors.initials: LJ
authors.lastname: Bruce
authors.forename: Hannah C
authors.initials: HC
authors.lastname: Robinson
authors.forename: Hélène
authors.initials: H
authors.lastname: Guizouarn
authors.forename: Franck
authors.initials: F
authors.lastname: Borgese
authors.forename: Penny
authors.initials: P
authors.lastname: Harrison
authors.forename: May-Jean
authors.initials: MJ
authors.lastname: King
authors.forename: Jeroen S
authors.initials: JS
authors.lastname: Goede
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Coles
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Gore
authors.forename: Hans U
authors.initials: HU
authors.lastname: Lutz
authors.forename: Romina
authors.initials: R
authors.lastname: Ficarella
authors.forename: D Mark
authors.initials: DM
authors.lastname: Layton
authors.forename: Achille
authors.initials: A
authors.lastname: Iolascon
authors.forename: J Clive
authors.initials: JC
authors.lastname: Ellory
authors.forename: Gordon W
authors.initials: GW
authors.lastname: Stewart
mesh_terms: D012856:4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid / Q000494:pharmacology; D019943:Amino Acid Substitution; D000743:Anemia, Hemolytic / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001457:Anion Exchange Protein 1, Erythrocyte / Q000235:genetics* / Q000378:metabolism; D001565:Benzoates / Q000494:pharmacology; D001692:Biological Transport; D002412:Cations / Q000378:metabolism*; D002463:Cell Membrane Permeability; D002712:Chlorides / Q000378:metabolism*; D004176:Dipyridamole / Q000494:pharmacology; D004912:Erythrocytes / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D009865:Oocytes / Q000166:cytology / Q000378:metabolism; D010375:Pedigree; D010671:Phenylurea Compounds / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D012313:RNA / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*; D013103:Spherocytosis, Hereditary / Q000235:genetics; D014982:Xenopus laevis
chemical_list: D001457:Anion Exchange Protein 1, Erythrocyte; D001565:Benzoates; D002412:Cations; D002712:Chlorides; D010671:Phenylurea Compounds; D010726:Phosphodiesterase Inhibitors; D012856:4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid; D012313:RNA; D004176:Dipyridamole; C405615:NS 1652; D012964:Sodium; D011188:Potassium