Abstract

The first two mutations causing hereditary glucose-6-phosphate isomerase (GPI) deficiency associated with chronic nonspherocytic hemolytic anemia in nonhuman mammals are described in the mouse. As in humans, the hemolytic syndrome, which is characterized by a diminished erythrocyte number, lower hematocrit, lower hemoglobin, higher number of reticulocytes and plasma bilirubin concentration, as well as increased liver- and spleen-somatic indices, was exclusively manifested in homozygous mutants. In comparison with wild type, heterozygous individuals exhibited neither hematologic differences nor alterations of other physiologic parameters, including plasma concentration of glucose, pyruvate and lactate, body weight, organo-somatic indices of liver, lung, kidney, spleen, and heart, as well as viability. Glycolytic intermediates, adenine nucleotides, and metabolic rate were not significantly altered in erythrocytes from heterozygotes. On the contrary, if allowance is made for the young erythrocyte population, homozygous mutant erythrocytes showed an increased concentration of glucose-6-phosphate and normal or decreased concentrations of glycolytic metabolites following the enzymatic block. The concentration of adenosine triphosphate and the glycolytic rate also appeared to be reduced. Homozygous anemic mice showed hepatosplenomegaly and typical adaptations to hypoxia, such as an elevated heart-somatic index and, for one mutant line, an enhanced lung-somatic index. Further, these animals were characterized by a marked reduction of body weight and an increase of lethality both correlated with the degree of enzyme deficiency in tissues. The latter findings were attributed to a reduced glycolytic capability of the whole organism caused by the enzyme defect in tissues, rather than representing secondary consequences of GPI deficiency in erythrocytes. The similarity in physicochemical and kinetic properties of the mutant murine proteins reported earlier with those of allozymes found in human GPI deficiency, as well as the comparable metabolic and physiologic consequences of this enzyme defect in mice and humans support that these murine mutants are excellent animal models for the human disease.

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