Temperature effects on cation transport in hereditary stomatocytosis and allied disorders

Abstract

The conditions known as 'hereditary stomatocytosis and allied syndromes' comprise a group of dominantly inherited human haemolytic anaemias characterized by a plasma membrane 'leak' to the univalent cations Na and K, an example of a small but growing group of diseases where pathology can be directly attributed to abnormal membrane transport. A number of case reports in the different variants have alluded to temperature-related phenomena, including loss of K on storage at room temperature (giving 'pseudohyperkalaemia') and lysis of cells when stored in the cold ('cryohydrocytosis'). This review collects together published studies of these temperature effects, which show very major differences in the 'leak' K transport. Two main variations on normal emerge: a 'shallow slope' type, in which the flux shows an abnormally low dependence on temperature in the range 37-20 degrees C, and 'high minimum', in which the minimum in this flux, which occurs in normal cells at 8 degrees C, is shifted up to 23 degrees C. These temperature studies provide a powerful method for phenotypic characterization.

The GPA-dependent, spherostomatocytosis mutant AE1 E758K induces GPA-independent, endogenous cation transport in amphibian oocytes

“…Increased cation leak in the oocyte might alternatively or additionally reflect endoplasmic reticulum stress specific to overexpression of AE1 E758K, as reported for oocyte overexpression of pathogenic mutants of the voltage-gated Ca 2ϩ channel Ca V 2.2 associated with episodic ataxia-2 (39), and elicited even by physiological Ca V 2.2 inhibition by either of the two auxiliary channel subunits ␥ 2 or ␥ 3 (42). Either interpretation is compatible with elevated cation permeability of human erythrocytes subjected to stress conditions such as thalassemia and dyserythropoietic anemia (53) or of normal red blood cells exposed to oxidizing agents or to replacement of extracellular Cl Ϫ or Na ϩ by impermeant ions (13,16).…”

“…However, H734R red blood cells did exhibit elevated, abnormally regulated K ϩ -Cl Ϫ cotransport (KCC) activity and increased K ϩ (Na ϩ )/H ϩ exchange activity. Earlier investigations of HSt cryohydrocytosis in red blood cells from patients later shown to be heterozygous for AE1 H734R also revealed increased Na ϩ pump activity, as well as increased cation-Cl Ϫ cotransport activity (26) [as measured, likely a sum of Na ϩ -K ϩ -2Cl Ϫ cotransport (NKCC) and KCC activities (13)]. HSt red blood cells from patients heterozygous for AE1 G796R also exhibited increased activities of KCC, NKCC, and Na ϩ /H ϩ exchange (27), in addition to increased membrane association of Lyn and Syk kinases and increased tyrosine phosphorylation of multiple membrane proteins.…”

Absence of CD47 in protein 4.2-deficient hereditary spherocytosis in man: an interaction between the Rh complex and the band 3 complex

“…48 In man, protein 4.2 mutations seem unlikely to be a cause of leaky red cell conditions of the hereditary stomatocytosis class. 49 The dissimilar consequences of the absence of protein 4.2 in mouse and man could arise either because there are different strengths of association of protein 4.2 with its several binding partners in the 2 species, or because of differences in the structure and organization of the protein 4.2-associated protein complexes.…”

Red Cell Membrane Disorders

“…Patients with features of both conditions have been reported with variability in the severity of permeability defects, stomatin deficiency, hemolysis, anemia, and numbers of stomatocytes. 26,27 This suggests that hereditary stomatocytosis is a complex collection of syndromes caused by various molecular defects.…”