IMMUNODEFICIENCY CAUSED BY PURINE NUCLEOSIDE PHOSPHORYLASE DEFICIENCY

Purine nucleoside phosphorylase (PNP) is a key enzyme in the purine salvage pathway with adenosine deaminase (ADA). Inherited deficiency of either one of two purine salvage enzymes results in severe combined immunodeficiency (SCID) in humans. 32,33,50 One of the striking features of ADA and PNP deficiencies is the selective effect on the immune system, although the activities of these enzymes are missing in every cell in the body. 50 The biochemical mechanism(s) explaining the pathology of PNP deficiency attempts to address the specificity of this disease toward the immune system. 50,68 Enzyme deficiencies can cause deleterious phenotypes as a result of lack of product of the enzymatic reaction or as a consequence of the cytotoxicity of the accumulating substrates. The lack of products in PNP deficiency is unlikely to contribute to the immune deficiency because deficiency of the next enzyme in the purine salvage pathway hypoxanthine-guanine phosphoribosyl transferase (HGPRT) causes Lesch-Nyhan syndrome with normal immune function. 62 Of the four purine nucleoside substrates of the PNP reaction, inosine, deoxyinosine, guanosine, and deoxyguanosine, only deoxyguanosine has an alternative metabolic fate (i.e., phosphorylation by deoxyguanosine kinase) (Fig. 1). 28,90 Deoxyguanosine is the only logical candidate to mediate the lymphoid abnormalities observed in PNP deficiency. The challenge remains to explain the metabolic, biochemical, and cellular mechanisms that lead to the unique lymphoid specificity of PNP deficiency despite its ubiquitous expression.