GCK – Maturity-onset diabetes of the young type 2 (MODY2)

Glucokinase (GCK) encodes the key pancreatic β-cell glucose sensor that phosphorylates glucose to glucose-6-phosphate. Heterozygous inactivating variants in GCK cause a stable, mild fasting hyperglycemia designated as MODY2 (PMID:23155715). This autosomal dominant condition manifests from birth and typically requires only dietary management.

Extensive genetic studies have confirmed autosomal dominant inheritance with high penetrance. Over 260 unrelated probands across diverse populations harbor GCK variants, with multi-family segregation in cohorts such as 103 Czech probands (PMID:20337973) and 79 Turkish probands (PMID:29056535). Segregation analyses include 23 Norwegian probands and 33 affected relatives (PMID:18399931).

The variant spectrum encompasses missense (e.g., c.676G>A (p.Val226Met)), nonsense, frameshift, and splice-site changes. Founder effects include p.Val226Met in French Canadians (PMID:17079173) and recurrent p.Glu40Lys in the Czech population (PMID:20337973). Variants cluster throughout exons altering kinetics or stability.

Phenotypic spectrum is remarkably consistent: lifelong, nonprogressive fasting hyperglycemia with mild glucose excursions on OGTT, low microvascular risk, and normal or near-normal HbA1c. Rarely, contiguous gene deletions including GCK present with additional neurological features such as seizures and intellectual disability (PMID:22043488).

Functional assays of recombinant GCK mutants reveal reduced Vmax, increased S0.5 for glucose, impaired thermal stability, and altered interactions with glucokinase regulatory protein (GKRP). For example, p.Thr209Met and p.Arg36Trp exhibit 3- to 8-fold S0.5 increases (PMID:10426385), while p.Glu265Lys destabilizes protein structure (PMID:16173921). Cellular studies show defective cytosolic–nuclear shuttling (PMID:17186219) and variable response to pharmacological activators (PMID:36520489).

Together, genetic and experimental data establish haploinsufficiency of GCK as the mechanism for MODY2. Definitive molecular diagnosis guides clinical management by avoiding unnecessary pharmacotherapy. Early genetic testing in mild hyperglycemia facilitates appropriate counseling and long-term follow-up.

References

• Diabetes • 1999 • Characterization of glucokinase mutations associated with maturity-onset diabetes of the young type 2 (MODY-2): different glucokinase defects lead to a common phenotype. PMID:10426385
• Molecular genetics and metabolism • 2007 • Prevalence and clinical phenotype of the p.Val226Met glucokinase gene mutation in French Canadians in Quebec, Canada. PMID:17079173
• Pediatric diabetes • 2010 • Glucokinase diabetes in 103 families from a country-based study in the Czech Republic: geographically restricted distribution of two prevalent GCK mutations. PMID:20337973
• Gene • 2018 • Analysis of the GCK gene in 79 MODY type 2 patients: A multicenter Turkish study, mutation profile and description of twenty novel mutations. PMID:29056535
• Journal of pediatric endocrinology & metabolism : JPEM • 2012 • MODY2 caused by a novel mutation of GCK gene. PMID:23155715
• American journal of medical genetics. Part A • 2011 • MODY type 2 in Greig cephalopolysyndactyly syndrome (GCPS) as part of a contiguous gene deletion syndrome. PMID:22043488
• Diabetologia • 2007 • Functional analysis of human glucokinase gene mutations causing MODY2: exploring the regulatory mechanisms of glucokinase activity. PMID:17186219
• FEBS letters • 2023 • A clinical mutation in glucokinase causing maturity-onset diabetes in the young type 2 increases enzyme activity. PMID:36520489

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