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Glucose-6-phosphate isomerase deficiency associated with nonspherocytic
hemolytic anemia in the mouse: an animal model for the human disease
S Merkle and W Pretsch
GSF-Forschungszentrum fur Umwelt und Gesundheit, Institut fur
Saugetiergenetik, Neuherberg, Germany.
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.
Volume 81,
Issue 1,
pp. 206-213,
01/01/1993
Copyright © 1993 by The American Society of Hematology
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