Pathogenic mechanisms in deficiencies of adenosine deaminase and purine nucleoside phosphorylase

Abstract

Inherited deficiencies of the enzymes adenosine deaminase (ADA) (E.C.3.5.4.4) and purine nucleoside phosphorylase (PNP) (E.C.2.4.2.1) recently have been associated with human immunodeficiency disease^1,2. There are two puzzling dilemmas to explain in these conditions. First, why are both enzyme deficiencies associated with similar clinical syndromes? Second, why do both diseases preferentially affect lymphoid development while sparing most other organ systems? None of the biochemical mechanisms proposed to explain ADA and PNP deficiency successfully answers both questions posed above^3-5. Recently we have collected evidence which suggests that lymphospecific toxicity in ADA and PNP deficiency might result from the selective accumulation in lymphoid tissues, particularly the thymus, of toxic deoxyribonucleotides, mediated by deoxyribonucleoside kinase(s).