MOLECULAR-BIOLOGY OF AMP-DEAMINASE DEFICIENCY

In man, there are at least four isoforms of adenosine monophosphate deaminase (AMPD): myoadenylate deaminase in skeletal muscle, the L isoform in liver, and the E1 and E2 isoforms in erythrocytes. Myoadenylate deaminase is encoded by the AMPD1 gene located on chromosome 1 p13-p21, the L isoform by the AMPD2 gene, and both isoforms in erythrocytes by the AMPD3 gene. Myoadenylate deaminase deficiency is found in 2-3% of all muscle biopsies. The inborn type of myoadenylate deaminase deficiency is caused by a single mutant allele harbouring two mutations: C34-T (Gln-->Stop) and C143-->T (Pro-48-->Leu). Population studies revealed a frequency of the mutant allele of 0.12 in Caucasian Americans and Germans. The C34-->T mutation is located in exon 2, which is alternatively spliced in part of the AMPD1 transcript in human muscle. Since the second mutation does not affect enzyme function, alternatively spliced mRNA encodes a catalytically active enzyme. Only one patient with a disorder linked to liver AMPD has been described so far. In this patient the decreased inhibition of this enzyme by GTP resulted in the uric acid overproduction and gout. A complete lack of erythrocyte AMPD activity is found in asymptomatic subjects. The molecular basis of both disorders is not yet known.