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Chromosomal mapping and mutational analysis of the coding region of the glycogen synthase kinase-3alpha and beta
L Hansen1, K C Arden, S B Rasmussen
1Steno Diabetes Center and Hagedorn Research Institute, Copenhagen, Denmark.
Abstract:
Activation of glycogen synthesis in skeletal muscle in response to insulin results from the combined inactivation of glycogen synthase kinase-3 (GSK-3) and activation of the protein phosphatase-1, changing the ratio between the inactive phosphorylated state of the glycogen synthase to the active dephosphorylated state. In a search for genetic defects responsible for the decreased insulin stimulated glycogen synthesis seen in patients with non-insulin-dependent diabetes mellitus (NIDDM) and their glucose-tolerant first-degree relatives we have performed mutational analysis of the coding region of the 2 isoforms of GSK-3alpha and GSK-3beta in 72 NIDDM patients and 12 control subjects. No structural changes were detected apart from a few silent mutations. Mapping of the GSK-3alpha to chromosome 19q13.1-13.2 and the GSK-3beta to chromosome 3q13.3-q21 outside known genetic loci linked to NIDDM further makes it unlikely that these genes are involved in the pathogenesis of common forms of NIDDM.
Insights
Genetic analysis of glycogen synthase kinase-3 (GSK-3) isoforms in non-insulin-dependent diabetes mellitus (NIDDM) patients revealed no significant mutations. These GSK-3 genes are unlikely to be involved in the common forms of NIDDM.
Area of Science:
- Biochemistry
- Genetics
- Endocrinology
Background:
- Insulin-stimulated glycogen synthesis in skeletal muscle involves inactivating glycogen synthase kinase-3 (GSK-3) and activating protein phosphatase-1.
- This process alters the phosphorylation state of glycogen synthase, shifting it from inactive to active forms.
- Decreased insulin-stimulated glycogen synthesis is observed in non-insulin-dependent diabetes mellitus (NIDDM).
Purpose of the Study:
- To investigate potential genetic defects in GSK-3 isoforms (GSK-3alpha and GSK-3beta) as a cause for reduced insulin-stimulated glycogen synthesis in NIDDM.
- To analyze the coding regions of GSK-3alpha and GSK-3beta in NIDDM patients and their relatives.
Main Methods:
- Mutational analysis of the coding regions of GSK-3alpha and GSK-3beta.
- Study included 72 NIDDM patients and 12 control subjects.
- Genetic mapping of GSK-3alpha and GSK-3beta loci.
Main Results:
- No significant structural mutations were detected in GSK-3alpha or GSK-3beta coding regions, apart from a few silent mutations.
- GSK-3alpha was mapped to chromosome 19q13.1-13.2 and GSK-3beta to chromosome 3q13.3-q21.
- These gene locations are outside known genetic loci associated with NIDDM.
Conclusions:
- The GSK-3alpha and GSK-3beta genes are unlikely to play a significant role in the pathogenesis of common forms of NIDDM.
- Further research may be needed to identify other genetic factors contributing to impaired glycogen synthesis in NIDDM.