The recognized association of an inherited deficiency of adenosine deaminase (ADA) activity and an autosomal recessive form of severe combined immunodeficiency disease has stimulated interest in the genetic nature of the enzyme deficiency with respect to the pathogenesis of immune dysfunction. Our approach to a better understanding of the expression and regulation of this enzyme in normal, abnormal, and genetically deficient states will focus on: (1) defining the primary structure of normal human ADA and the nature of its post-translational modiflcation; (2) characterizing the kinetic and physical properties of normal and mutant forms of ADA in cultured cells; and (3) identifying the type and site(s) of mutation in ADA protein from patients with this enzyme deficiency. Current progreas toward our objectives include cloning ADA cDNA and determining the complete primary ADA amino acid sequence. Studies of partial ADA deficient patients have revealed transcriptional, translational, and post-translational defects which serve to explain the steady state enzyme level expressed in these subjects. It is hoped that our goal-directed approach will allow a more precise definition of structuraI characteristics and processing of ADA protein in normal and genetically deficient patients. (LB)
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