Abstract
Adenosine deaminase (ADA, EC 3.5.4.4) is an essential enzyme of purine metabolism that is expressed at very high levels in the murine placenta where it accounts for over 95% of the ADA present at the fetal gestation site. We have recently shown that ADA-deficient fetuses, which also lack ADA in their adjoining placentas, die during late fetal development in association with profound purine metabolic disturbances and hepatocellular impairment. We have now investigated the potential importance of placental ADA by genetically restoring the enzyme to placentas of ADA-deficient fetuses. This genetic engineering strategy corrected most of the purine metabolic disturbances, prevented serious fetal liver damage, and rescued the fetuses from perinatal lethality. Our findings suggest that placental ADA is important for murine fetal development and illustrate a general strategy for the tissue specific correction of phenotypes associated with null mutations in mice.
Highlights
Introductionadenosine deaminase (ADA) is an essential enzyme of purine metabolism that is expressed at very high levels in trophoblasts of the murine placenta [6, 7]
In the current study we show that genetically restoring adenosine deaminase (ADA) enzymatic activity to placentas of ADA-deficient fetuses prevents most of the purine metabolic disturbances seen in ADAdeficient fetuses
This suggests that disturbances in purine metabolism may be responsible for the liver damage and perinatal lethality seen in ADA-deficient fetuses [8, 9]
Summary
ADA is an essential enzyme of purine metabolism that is expressed at very high levels in trophoblasts of the murine placenta [6, 7]. Recent evidence suggests that ADA is essential during fetal stages of development. ADA-deficient fetuses, which lacked ADA in trophoblasts of their adjoining placentas, died perinatally in association with profound purine metabolic disturbances and hepatocellular impairment [8, 9]. Considering that greater than 95% of ADA enzymatic activity found in the fetal gestation site resides in trophoblasts of the placenta, it is likely that placental ADA plays an essential role during fetal development. We show that genetically restoring ADA to placentas of ADA-deficient fetuses rescued them from perinatal lethality, thereby providing compelling evidence for the importance of placental ADA for fetal development
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