PHOSPHOGLUCOMUTASE-1 - A GENE WITH 2 PROMOTERS AND A DUPLICATED 1ST EXON

In view of its central role in glycolysis and gluconeogenesis and its polymorphic genetic variability, the phosphoglucomutase 1 (PGM1) gene in man has been the target of protein structural studies and genetic a nalysis for more than 25 years. We have now isolated genomic clones co ntaining the complete PGM1 gene and have shown that it spans over 65 k b and contains 11 exons. We have also shown that the sites of the two mutations which form the molecular basis for the common PGM1 protein p olymorphism lie in exons 4 and 8 and are 18 kb apart. Within this regi on there is a site of intragenic recombination. We have discovered two alternatively spliced first exons, one of which, exon 1A, is transcri bed in a wide variety of cell types; the other, exon 1B, is transcribe d in fast muscle. Exon 1A is transcribed from a promoter which has the structural hallmarks of a housekeeping promoter but lies more than 35 kb upstream of exon 2. Exon 1B lies 6 kb upstream of exon 2 within th e large first intron of the ubiquitously expressed PGM1 transcript. Th e fast-muscle form of PGM1 is characterized by 18 extra amino acid res idues at its N-terminal end. Sequence comparisons show that exons 1A a nd 1B are structurally related and have arisen by duplication.