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Prenatal expression of a lethal genetic defect in carbohydrate metabolism in mice
Abstract:
Mouse fetuses homozygous for the lethal cab (cardiac abnormal) mutation are characterized by pleiotropic effects that lead to immediate postnatal death. Mutant fetuses have only 4% of the normal amount of hepatic glycogen and 39% of the normal cardiac glycogen reserve, coupled with lower specific activities of glycogen synthase and phosphorylase. Analysis with the periodic acid-Schiff reagent histochemical stain demonstrated that cab homozygotes also have reduced amounts of structural polysaccharides. One of the most distinctive mutant phenotypic traits is severe prenatal hypoglycemia, with average (+/-SEM) plasma glucose concentrations of 0.35 +/- 0.14 mM in late fetuses compared to 3.47 +/- 0.69 mM in normal littermates. Compromise of glucose transport from dam to fetus or altered cellular glucose utilization was considered as a possible basis for the low extracellular and intracellular (hepatic) levels of glucose in mutants. Transport of the glucose analogue alpha-methyl[14C]glucoside by the placenta of cab homozygotes is normal. However, metabolism of [14C]glucose by mutant cells yields only 20% of the normal amount of 14CO2. This reduced efficiency of glucose metabolism is correlated with lower ATP concentrations in mutant organs. Aberrant glucose utilization may account for the pleiotropic features of the cab syndrome.
Insights
The lethal cardiac abnormal (cab) mutation causes severe prenatal hypoglycemia in mice due to impaired glucose metabolism, leading to postnatal death. This study reveals abnormal glucose utilization as the cause of the cab syndrome.
Area of Science:
- Developmental biology
- Molecular genetics
- Biochemistry
Background:
- The lethal cardiac abnormal (cab) mutation in mice results in pleiotropic effects and immediate postnatal death.
- Mutant fetuses exhibit significantly reduced hepatic and cardiac glycogen reserves, with decreased glycogen synthase and phosphorylase activity.
Purpose of the Study:
- To investigate the underlying cause of severe prenatal hypoglycemia observed in mouse fetuses homozygous for the cab mutation.
- To determine whether impaired glucose transport or altered cellular glucose utilization contributes to the cab syndrome.
Main Methods:
- Histochemical analysis using periodic acid-Schiff reagent to assess structural polysaccharides.
- Measurement of plasma glucose concentrations in late-term fetuses.
- Assessment of placental glucose analogue transport.
- Quantification of [14C]glucose metabolism to 14CO2 and ATP concentrations in mutant organs.
Main Results:
- Cab homozygotes display severe prenatal hypoglycemia (0.35 mM vs. 3.47 mM in controls).
- Placental transport of a glucose analogue is normal, ruling out impaired maternal-fetal glucose transfer.
- Mutant cells metabolize [14C]glucose to 14CO2 at only 20% of the normal rate, correlating with lower ATP levels.
- Reduced glucose metabolism and ATP concentrations suggest aberrant cellular glucose utilization.
Conclusions:
- Aberrant glucose utilization, rather than impaired transport, is the primary defect in the cab syndrome.
- The reduced efficiency of glucose metabolism and subsequent energy deficit likely underlie the pleiotropic features and lethality of the cab mutation.