Characterization of the human and rat myoadenylate deaminase genes.

AMP deaminase is an ubiquitous enzyme in eukaryotic cells, and tissue-specific isoforms are produced in mammals by differential expression of the two genes which encode this enzyme activity as well as by alternative splicing of the primary transcript of one of these genes. Deficiency of this enzyme activity is one of the most common causes of metabolic myopathy in man. To provide a framework for understanding the molecular basis of this inherited disorder and the mechanisms responsible for regulating the expression of this enzyme activity, both the human and rat muscle-specific genes for AMP deaminase have been cloned and partially sequenced. Comparison of the two genes shows a high degree of conservation of sequence and structural organization. The two genes share the following characteristics: 1) both are approximately 20 kilobases in size, have identical exon/intron boundaries, and exhibit similar intron/exon structural organization; 2) the transcription start site is located at the same position in both genes, and comparison of 5'-flanking sequences reveals four highly conserved domains that together contain the information necessary for muscle-specific expression of a receptor cDNA; 3) coding sequences are 88% identical and the 5'-untranslated regions are 67% identical; 4) both genes have extremely short 3'-untranslated regions (13-17 nucleotides); 5) highly conserved intervening sequences of several hundred nucleotides surround most exon/intron boundaries. In situ hybridization and analysis of human-mouse somatic cell hybrids have localized the human gene (designated AMPD1) to chromosome 1 in the region p13-p21. The implications of these structural properties for identifying functional domains in the AMP deaminase peptide, regulation of expression of this gene, and inheritance of AMP deaminase deficiency are discussed.