METABOLIC AND IMMUNOLOGICAL CONSEQUENCES OF LIMITED ADENOSINE-DEAMINASE EXPRESSION IN MICE

Adenosine deaminase (ADA; EC 3.5.4.4) deficiency in humans is an autos omal recessive genetic disorder that results in severe combined immuno deficiency disease, ADA-deficient mice generated by targeted gene disr uption die perinatally, preventing postnatal analysis of ADA deficienc y. We have recently rescued ADA-deficient fetuses from perinatal letha lity by expression of an ADA minigene in the placentas of ADA-deficien t fetuses, thus generating postnatal mice admissible to analysis of AD A deficiency, The minigene used also directed ADA expression to the fo restomach postnatally, producing adult animals that lacked ADA enzymat ic activity in all tissues outside the gastrointestinal tract, Mice wi th limited ADA expression exhibited profound disturbances in purine me tabolism, including thymus-specific accumulations of deoxyadenosine an d dATP, and inhibition of S-adenosylhomocysteine hydrolase in the thym us, spleen, and, to a lesser extent, the liver, Lymphopenia and mild i mmunodeficiency were associated with these tissue-specific metabolic d isturbances, These mice represent the first genetic animal model for A DA deficiency and provide insight into the tissue-specific requirement s of ADA.