Proceedings of The Physiological Society
University of Oxford (2011) Proc Physiol Soc 23, C31
Human genetic mutations causing increased permeability to monovalent cations across the red cell membrane
G. W. Stewart1, H. Guizouarn2, L. J. Bruce3
1. Medicine, University College London, London, United Kingdom. 2. Institut de Biologie du Developpement et Cancer, Universite de Nice-CNRS, Nice, France. 3. Bristol Institute for Transfusion Sciences, Bristol, United Kingdom.
The ‘hereditary stomatocytoses’ comprise a group of heterogeneous human haemolytic anaemias, in all of which the red cell membrane ‘leaks’ the monovalent cations sodium and potassium, compromising the osmotic balance in the cell (Stewart GW, 2004). Often, different conditions within the group can usefully be distinguished on the basis of the temperature dependence of the increased cation permeability. So far we have identified three human genes that can be mutated in these conditions. These are: SLC4A1, coding for the band 3 anion exchanger, AE1 (Bruce LJ et al., 2005); RHAG, coding for the Rh-associated glycoprotein, a probable gas transporter (Bruce LJ et al., 2009); and SLC2A1, coding for the GLUT1 glucose transporter (JF Flatt, H Guizouarn, NM Burton, F Borgese, RJ Tomlinson, RJ Forsyth, SA Baldwin, BE Levinson, P Quittet, P Aguilar-Martinez, J Delaunay, GW Stewart, LJ Bruce, unpublished). All of these proteins are integral membrane proteins with 10-12 membrane-spanning domains, which are expressed in the red cell membrane. In no case is the ‘physiological’ substrate a cation, but something quite different: an anion, a gas, or a carbohydrate. The mutations are either substitutions or deletions of single amino acids. In each case we have shown that the mutant protein, when expressed in oocytes, carries an excess of cations. These are all high-copy-number proteins of the red cell membranes (>500,000 per cell). Red cells have very slow cation transport rates (there are only about 350 NaK pump units cell per cell). The cation leak turnover number of these mutants must be much lower than the turnover for the physiological substrate. Nevertheless the leak is such that the pump cannot cope, destabilising the osmotic balance of the cell. RhAG is expressed solely in the red cell, while AE1 is expressed in red cell and kidney. These patients show a clinical picture of haemolytic anaemia only. GLUT1 is expressed in the red cell membrane, the blood brain barrier and epithelium of lens, and these patients have neurological problems and cataracts in addition to haemolysis (Fricke B et al., 2004). All of these proteins are representatives of large families of proteins widely expressed in the body. Parallel mutations in homologues from different tissues could cause other forms of clinical pathology.
Where applicable, experiments conform with Society ethical requirements