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 adenosin e deaminase (ADA). in humans, absence of ADA causes severe combined im munodeficiency. In contrast, ADA-deficient mice die perinatally with m arked liver-cell degeneration, but lack abnormalities in the thymus. T he ADA substrates, adenosine and deoxyadenosine, are increased in ADA- deficient mice. Adenine deoxyribonucleotides are only modestly elevate d, whereas S-adenosylhomocysteine hydrolase activity is reduced more t han 85%. Consequently, the ratio of S-adenosylhomocysteine (AdoMet) to S-adenosyl homocysteine (AdoHcy) is reduced threefold in liver. We co nclude that ADA plays a more critical role in murine than human fetal development. me murine liver pathology may be due to AdoHcy-mediated i nhibition of AdoMet-dependent transmethylation reactions.