PATHOGENESIS OF AMP DEAMINASE DEFICIENCY

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AMP deaminase and the purine nucleotide cycle of which it is one component are important for energy metabolism in may tissues. The role of this cycle in energy metabolism has been best studied in skeletal muscle where the activities of these enzymes are particularly high, tissue-specific isoforms are found, and flux through the cycle increases dramatically with exercise. The clinical relevance of this cycle in skeletal muscle is highlighted by the myopathy which develops in patients with inherited deficiencies of nucleotide cycle enzymes. AMP deaminase deficiency, the most common defect in this cycle, is associated with an exercise-related myopathy. The purpose of these studies is to understand the regulation of AMP deaminase expression in normal and pathological conditions. AMP deaminase exists in multiple isoforms, some of which are tissue- specific. One set of projects is designed to use isoform specific anti-sera and nucleic acid probes to study developmental and tissue-specific control of isoform expression in animal models and a tissue culture model of myocyte differentiation. Another set of experiments is designed to assess the function of different domains of AMP deaminase through the use of in vivo and in vitro expression vectors with the goal of localizing isoform-specific properties to different domains. A third set of projects is designed to determine the molecular bases of inherited and acquired deficiencies of AMP deaminase through the study of patients using isoform-specific and nucleic acid probes. Results of these studies have direct relevance to understanding the control of AMP deaminase and the purine nucleotide cycle in normal conditions and to understanding the pathogenesis of AMP deaminase deficiency. The results may have broader significance by providing additional insight to processes which control myocyte differentiation.