GENETIC-CONTROL OF ERYTHROCYTE VOLUME REGULATION - EFFECT OF A SINGLE-GENE (ROL) ON CATION METABOLISM

In laboratory mice we previously defined a gene, rol (resistance to osmotic lysis), based on its effect on erythrocyte osmotic fragility. Here we report a physiological characterization of rol gene action utilizing congenic strains developed for the purpose; these two strains have a common genetic background and differ only by the two alleles of rol, susceptible (rol(s)) or resistant (rol(r)). In comparison to rol(s/s) erythrocytes, rol(r/r) cells have a reduced mean cell volume, a higher mean corpuscular hemoglobin concentration and hemolytic volume, and respond differently to swelling induced by ion influx. Rol(r/r) erythrocytes also have reduced cell water and K, which are associated with a threefold higher activity of the Na-K-Cl cotransporter (measured as ouabain-resistant, bumetanide-sensitive Rb-86 influx) and 30% higher Na pump activity. Apart from differences in ion transport and water content, the content of 2,3-diphosphoglycerate (2,3-DPG) in rol(r/r) cells is 15% lower than in rol(s/s) ones. Analyses of membrane structural components revealed no rol-associated differences in their phospholipid or fatty acid content, nor were strain differences evident among the membrane and cytoskeletal proteins and their postranslational modifications (phosphorylation and fatty acylation). Rol is not the structural gene for either the alpha- or the beta-chain of hemoglobin and has no effect on erythrocyte production or destruction. The concerted effect of rol variation on erythrocyte volume, water and cation content, cation cotransport, and 2,3-DPG levels is similar in many ways to the variation observed among individual humans for the same characteristics. These congenic mice differing at rol are likely to provide a simplified model to study the mechanism and pathophysiological consequences of such variation.