GCK – Maturity-onset diabetes of the young

Glucokinase (GCK, HGNC:4195) is definitively associated with Maturity-onset diabetes of the young (MODY, [MONDO:0018911]). Heterozygous inactivating GCK variants cause a stable, mild fasting hyperglycaemia phenotype inherited in an autosomal dominant fashion, with early onset and a primary defect in glucose-stimulated insulin secretion. ([PMID:1303265])

Inheritance is autosomal dominant with robust segregation: over 50 unrelated probands have been described, with at least 19 additional affected relatives across multiple three-generation families. In the original British pedigree, the c.896G>C (p.Gly299Arg) variant co-segregated with disease in nine relatives. ([PMID:1303265])

The variant spectrum includes more than 30 distinct missense substitutions, splice-site changes, small insertions/deletions and exon-level rearrangements. Examples include c.896G>C (p.Gly299Arg), c.562G>A (p.Ala188Thr), c.775G>A (p.Ala259Thr), c.608T>C (p.Val203Ala) and large deletions of exons 7–9. ([PMID:1303265]; [PMID:8314448]; [PMID:9713013])

Clinically, GCK-MODY presents with mild, non-progressive fasting hyperglycaemia (5.5–8 mmol/L) often detected incidentally or by family screening. Patients rarely require pharmacotherapy; dietary management suffices, and microvascular complications are uncommon. Genetic diagnosis spares unnecessary insulin or sulfonylurea therapy and guides family counselling. ([PMID:16059790])

Functional studies demonstrate that inactivating GCK mutations increase the S0.5 for glucose and/or reduce Vmax, impairing enzyme kinetics. Mouse models carrying activating or inactivating alleles recapitulate hyper- or hypoglycaemia, confirming GCK’s key role as a pancreatic glucose sensor. ([PMID:8325892]; [PMID:8446612]; [PMID:15161764])

Collectively, abundant genetic and experimental evidence supports a definitive GCK–MODY2 association. Molecular testing for GCK variants enables precise diagnosis, individualised management and informed genetic counselling.

References

• Nature Genetics • 1992 • Missense glucokinase mutation in maturity-onset diabetes of the young and mutation screening in late-onset diabetes. PMID:1303265
• Diabetologia • 1993 • Type 2 (non-insulin-dependent) diabetes mellitus associated with a mutation of the glucokinase gene in a Japanese family. PMID:8314448
• Archives of Disease in Childhood • 1998 • Genetic testing for maturity onset diabetes of the young in childhood hyperglycaemia. PMID:9713013
• The Journal of Biological Chemistry • 1993 • Structure/function studies of human beta-cell glucokinase. Enzymatic properties of a sequence polymorphism, mutations associated with diabetes, and other site-directed mutants. PMID:8325892
• Proceedings of the National Academy of Sciences USA • 1993 • Glucokinase mutations associated with non-insulin-dependent (type 2) diabetes mellitus have decreased enzymatic activity: implications for structure/function relationships. PMID:8446612
• Diabetes • 2004 • A new mouse model of type 2 diabetes, produced by N-ethyl-nitrosourea mutagenesis, is the result of a missense mutation in the glucokinase gene. PMID:15161764

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