Adenosine-deaminase-deficient mice die perinatally and exhibit liver-cell degeneration, atelectasis and small intestinal cell death

We report the generation and characterization of mice lacking adenosine deaminase (ADA). In humans, absence of ADA causes severe combined immunodeficiency. In contrast, ADA–deficient mice die perinatally with marked liver–cell degeneration, but lack abnormalities in the thymus. The ADA substrates, adenosine and deoxyadenosine, are increased in ADA–deficient mice. Adenine deoxyribonucleotides are only modestly elevated, whereas S–adenosylhomocysteine hydrolase activity is reduced more than 85%. Consequently, the ratio of S–adenosylhomocysteine (AdoMet) to S–adenosyl homocysteine (AdoHcy) is reduced threefold in liver. We conclude that ADA plays a more critical role in murine than human fetal development. The murine liver pathology may be due to AdoHcy–mediated inhibition of AdoMet–dependent transmethylation reactions.