Abstract
The hereditary stomatocytoses are a series of dominantly-inherited hemolytic anemias in which the permeability of the erythrocyte membrane to monovalent cations is pathologically increased. The causative mutations for some forms of hereditary stomatocytosis have been found in the transporter protein genes, RHAG and SLC4A1. Glut1 deficiency syndromes (glut1DS) result from mutations in SLC2A1, encoding glucose transporter 1 (glut1). Glut1 is the major glucose transporter in the mammalian blood-brain barrier and glut1DS are manifested by an array of neurological symptoms. We have previously reported two cases of stomatin-deficient cryohydrocytosis (sdCHC), a very rare form of stomatocytosis associated with a cold-induced cation leak, hemolytic anemia and hepatosplenomegaly but also with cataracts, seizures, mental retardation and movement disorder. We now show that sdCHC is associated with mutations in SLC2A1 that cause both loss of glucose transport and a cation leak, as shown by expression studies in Xenopus oocytes. Based on a 3D model of glut1, we propose potential mechanisms underlying the phenotypes of the two mutations found. We investigated the loss of stomatin during erythropoiesis and find this occurs during reticulocyte maturation and involves endocytosis. The molecular basis of the glut1DS, paroxysmal exercise-induced dyskinesia (PED) and sdCHC phenotypes are compared and discussed.