Isolation and characterization of the human muscle glycogen synthase gene.

Impaired glycogen synthase (GS) activity in skeletal muscle has been considered to be an inherited trait in patients with non-insulin-dependent diabetes mellitus (NIDDM). We therefore isolated the human muscle GS gene from genomic libraries and determined the genomic structure. The entire coding region, the 5'-flanking region, and the exon-intron boundaries were sequenced. The gene consists of 16 exons spanning approximately 27 kb of DNA and exists as a single copy in the human genome. The negatively charged parts with all known phosphorylation sites were coded by the first and the last exon. A single transcription initiation site was located 167 nucleotides upstream of the initiation codon. All of the exons and the putative promoter region were analyzed by single-strand conformation polymorphism in 30 insulin-resistant Finnish NIDDM patients, and three polymorphic sites were found. A missense mutation Gly464/Ser in exon 11 was found in 2 of 228 NIDDM patients screened but in 0 of 154 control subjects. These two patients were characterized further by severe insulin resistance and premature arteriosclerosis. The characterization of the genomic structure of the human muscle GS gene will facilitate studies of its role in the development of insulin resistance and NIDDM.