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.
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.
Bruce
Lesley J
LJ
Bristol Institute for Transfusion Sciences, National Blood Service, Southmead, Bristol BS10 5ND, UK.
Robinson
Hannah C
HC
Guizouarn
Hélène
H
Borgese
Franck
F
Harrison
Penny
P
King
May-Jean
MJ
Goede
Jeroen S
JS
Coles
Suzanne E
SE
Gore
Daniel M
DM
Lutz
Hans U
HU
Ficarella
Romina
R
Layton
D Mark
DM
Iolascon
Achille
A
Ellory
J Clive
JC
Stewart
Gordon W
GW
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
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