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Sequence of the human glycogen-associated regulatory subunit of type 1 protein phosphatase and analysis of its coding region and mRNA level in muscle from patients with NIDDM

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Impaired insulin-stimulated glycogen synthesis of peripheral tissues is a characteristic feature of many patients with non-insulin-dependent diabetes mellitus (NIDDM) and their first-degree relatives with normal glucose tolerance, suggesting putative inherited defects in this metabolic pathway. In previous studies, we have failed to reveal mutations in the coding regions of the muscle-specific glycogen synthase gene and the three genes that encode the catalytic subunits of protein phosphatase 1 (PP1) as frequent causes of insulin resistance. Because the glycogen-associated regulatory subunit of protein phosphatase 1 (PP1 G-subunit) plays a key role in the insulin stimulation of glycogen synthesis and the activity of PP1 is decreased in insulin-resistant subjects, we have now cloned the human G-subunit cDNA to search for abnormalities in the corresponding gene (designated PPP1R3 in the human genome nomenclature) in patients with NIDDM. The human cDNA was isolated from a skeletal muscle cDNA library and was found to encode a 126-kDa protein, which shows 73% amino acid identity to the rabbit PP1 G-subunit. The human G-subunit cDNA from 30 insulin-resistant NIDDM patients was analyzed for genetic variations in the G-subunit by using single-stranded conformation polymorphism (SSCP) scanning of reversely transcribed mRNA. One variant SSCP profile was detected in the region encoding the COOH-terminal part of the PP1 G-subunit in only one NIDDM patient, and subsequent nucleotide sequencing showed a C to A transversion on one allele at base position 2792. This change predicts an amino acid substitution from alanine to glutamic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

Original languageEnglish
Issue number10
Pages (from-to)1234-41
Number of pages8
Publication statusPublished - Oct 1994

    Research areas

  • Amino Acid Sequence, Animals, Base Sequence, DNA Primers, Diabetes Mellitus, Type 2, Female, Glucose, Glycogen, Humans, Macromolecular Substances, Male, Middle Aged, Molecular Sequence Data, Muscles, Phosphoprotein Phosphatases, Polymerase Chain Reaction, Polymorphism, Genetic, Protein Phosphatase 1, RNA, Messenger, Rabbits, Reference Values, Sequence Homology, Amino Acid, Comparative Study, Journal Article, Research Support, Non-U.S. Gov't

ID: 52806195