Nature Genetics 37, 1258 - 1263 (2005)
Published online: 9 October 2005; | doi:10.1038/ng1656
Monovalent cation leaks in human red cells caused by single amino-acid substitutions in the transport domain of the band 3 chloride-bicarbonate exchanger, AE1Lesley J Bruce1, Hannah C Robinson2, Hélène Guizouarn3, Franck Borgese3, Penny Harrison4, May-Jean King1, Jeroen S Goede5, Suzanne E Coles4, Daniel M Gore4, Hans U Lutz6, Romina Ficarella7, D Mark Layton8, Achille Iolascon9, J Clive Ellory2
& Gordon W Stewart41
Bristol Institute for Transfusion Sciences, National Blood Service, Southmead, Bristol BS10 5ND, UK. 2
University Laboratory of Physiology, South Parks Road, Oxford OX1 3PT, UK. 3
Laboratoire de Physiologie des membranes Cellulaires, FRE 2721 CNRS-Université de Nice, Bâtiment de Sciences Naturelles, 28 av. Valrose, 06108 Nice, cedex 2, France. 4
Department of Medicine, University College London, University Street, London WC1E 6JJ, UK. 5
Department of Internal Medicine, Division of Hematology, University Hospital of Zurich, Sternwartstrasse 2, 8091 Zurich, Switzerland. 6
Institute of Biochemistry, ETH-Hoenggerberg, Schafmattstrasse 18, CH-8093 Zurich, Switzerland. 7
Telethon Institute of Genetics and Medicine, Via P. Castellino 111, 80131 Napoli, Italy. 8
Department of Haematology, Imperial College, Hammersmith Hospital, London W12 0HS, UK. 9
Department of Biochemistry and Medical Biotechnologies, CEINGE Biotecnologie Avanzante, Federico II University, Via Comunale Margherita 482, 80131 Napoli, Italy.
Correspondence should be addressed to Gordon W Stewart g.stewart@ucl.ac.uk 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 °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.
MORE ARTICLES LIKE THIS These links to content published by NPG are automatically generated.
|
