Stoffel, M. et al. Missense glucokinase mutation in maturity-onset diabetes of the young and mutation screening in late-onset diabetes. Nature Genet. 2, 153−156

Howard Hughes Medical Institute, University of Chicago, Illinois 60637.
Nature Genetics (Impact Factor: 29.35). 11/1992; 2(2):153-6. DOI: 10.1038/ng1092-153
Source: PubMed


We describe a codon 299 mutation in the glucokinase gene in a British pedigree with maturity-onset diabetes of the young (MODY) resulting in a substitution of glycine to arginine. One out of fifty patients diagnosed with classical late-onset type 2 diabetes mellitus was also found to have this mutation. All nine relatives of this patient who have inherited the mutation have type 2 diabetes, although six others without the mutation are also present with diabetes. The discovery that glucokinase mutations can cause MODY and was also found in ten affected members of a pedigree with type 2 diabetes in which MODY had not previously been considered indicates that diagnosis based on molecular pathology will be helpful in understanding the aetiology of type 2 diabetes.

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    • "This gene is located on the chromosome 7 (7p15.3-15.1) and contains 12 exons that encode the 465-amino-acid protein glucokinase[3]. Heterozygous inactivating mutations of the GCK gene lead to mild fasting hyperglycemia and diminished insulin secretion, along with decreased hepatic glucose uptake and glycogen synthesis[4]. "
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    ABSTRACT: Maturity onset diabetes of the young type 2 (MODY) is an inherited disorder due to mutations in glucokinase (GCK) gene, which lead to mild fasting hyperglycemia. Herein an otherwise healthy 9-year old boy with hyperglycemia is presented in whom the diagnosis of MODY2 was suspected. Genetic studies showed heterozygous inactivating GCK gene mutation in exon 8 (c.1010delA) in this patient. The same mutation was found in his father as well. The patient received some dietary advices without any medication. The identification of GCK mutation and diagnosis of MODY2 helps the clinicians to predict the disease course, prognosis and to exclude other types of diabetes.
    Full-text · Article · Apr 2013 · Iranian Journal of Pediatrics
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    • "GK gene is 52.15 kilo bases (kb) in length and is present on Chromosome 7 p13 with 12 exons and produces a transcript of 2.7 kb. A number of reports suggest that the existence of mutations in the coding region of GK is associated with MODY2 [3] [4] [5] [6] [7] [8] [9] [10] [11]. "
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    ABSTRACT: Glucokinase (GK) is the predominant hexokinase that acts as glucose sensor and catalyses the formation of Glucose-6-phosphate. The mutations in GK gene influence the affinity for glucose and lead to altered glucose levels in blood causing maturity onset diabetes of the young type 2 (MODY2) condition, which is one of the prominent reasons of type 2 diabetic condition. In view of the importance of mutated GK resulting in hyperglycemic condition, in the present study, molecular dynamics simulations were carried out in intact and 256 E-K mutated GK structures and their energy values and conformational variations were correlated. Energy variations were observed in mutated GK (3500 Kcal/mol) structure with respect to intact GK (5000 Kcal/mol), and it showed increased -turns, decreased -turns, and more helix-helix interactions that affected substrate binding region where its volume increased from 1089.152 Å to 1246.353 Å. Molecular docking study revealed variation in docking scores (intact = -12.199 and mutated = -8.383) and binding mode of glucose in the active site of mutated GK where the involvement of A53, S54, K56, K256, D262 and Q286 has resulted in poor glucose binding which probably explains the loss of catalytic activity and the consequent prevailing of high glucose levels in MODY2 condition.
    Full-text · Article · Feb 2013
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    • "The first one was the candidate gene approach, focused on a limited set of genes picked up for the mutation search based on their role in insulin secretion or insulin action. This strategy led to the discovery of the first monogenic diabetes genes—for example insulin receptor and glucokinase [13, 14]. It soon became clear that a more systematic strategy was necessary to increase the efficacy and success rate of the search for new genes. "
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    ABSTRACT: Monogenic diabetes constitutes a heterogeneous group of single gene disorders. The molecular background and clinical picture of many of these diseases have been described. While each of these forms is much less prevalent than multifactorial type 1 and type 2 diabetes mellitus (T2DM), together they affect millions of patients worldwide. Genetic diagnosis, which has become widely available, is of great clinical importance for patients with single gene diabetes. It helps to fully understand the pathophysiology of the disease, tailor the optimal hypoglycemic treatment, and define the prognosis for the entire family. Monogenic diabetes forms can be divided into 2 large groups, resulting from impaired insulin secretion or from an abnormal response to insulin. There are several lessons we have been taught by single-gene diabetes. We learned that the gene responsible for the occurrence of diabetes can be identified if an appropriate search strategy is used. In addition, discoveries of genes responsible for monogenic disorders pointed to them as susceptibility candidates for T2DM. Moreover, establishing that some families of proteins or biological pathways, such as transcription factors or potassium channel subunits, are involved in monogenic diabetes sparked research on their involvement in multifactorial diabetes. Finally, the example of single gene diabetes, particularly HNF1A MODY and permanent neonatal diabetes associated with the KCNJ11 and ABCC8 genes, all efficiently controlled on sulfonylurea, inspires us to continue the efforts to tailor individual treatment for T2DM patients. In this review paper, we summarize the impact of single gene disease discoveries on diabetes research and clinical practice.
    Preview · Article · Sep 2012 · Current Diabetes Reports
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