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GCK-MODY (MODY 2) Caused by a Novel p.Phe330Ser Mutation

DOI: 10.5402/2011/676549

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Maturity onset diabetes of the young (MODY) is a monogenic form of diabetes inherited as an autosomal dominant trait. The second most common cause is GCK-MODY due to heterozygous mutations in the GCK gene which impair the glucokinase function through different mechanisms such as enzymatic activity, protein stability, and increased interaction with its receptor. The enzyme normally acts as a glucose sensor in the pancreatic beta cell and regulates insulin secretion. We report here a three-generation nonobese family diagnosed with diabetes. All affected family members presented with mild hyperglycemia and mostly slightly elevated hemoglobin A1c values. Genetic testing revealed a novel heterozygous T → C exchange in exon 8 of the GCK gene which resulted in a phenylalanine330 TTC → serine (TCC)/p.Phe330Ser/F330S substitution. 1. Introduction MODY is a monogenic disease which accounts for 2–5% of all diabetes cases. The most frequent form is HNF-1α-MODY (MODY type 3), which is caused by mutations in the HNF1A gene encoding hepatic nuclear factor 1α. The second most frequent form is GCK-MODY (MODY type 2), which has been shown to be the result of mutations in the GCK gene [1]. The GCK gene maps to chromosome 7p15.3-p15.1 and consists of 12 exons that encode the 465-amino-acid protein glucokinase [2, 3], which is one of four members of the hexokinase family of enzymes. It catalyzes the phosphorylation of glucose as the first step of glycolysis. Glucokinase is exclusively expressed in mammalian liver and pancreatic islet beta cells. The enzyme plays an important regulatory role in glucose metabolism. As a glucose sensor, it regulates insulin secretion in the pancreatic β-cell by changing the glucose phosphorylation rate over a range of physiological glucose concentrations (4–15?mmoL/L; [4]). GCK gene mutations can cause both hypo- and hyperglycemia. Heterozygous inactivating mutations cause GCK-MODY, which mostly presents with mild hyperglycemia and is inherited in an autosomal dominant fashion [5, 6]. Usually, no diabetes-related complications such as nephropathy or retinopathy occur in patients with GCK-MODY. Homozygous or compound heterozygous inactivating GCK mutations result in a more severe phenotype presenting at birth as permanent neonatal diabetes mellitus [7–11]. Heterozygous activating GCK mutations, in contrast, cause persistent hyperinsulinemic hypoglycemia of infancy [12–16]. In 1992, GCK was the first MODY gene to be linked to disease in French and UK families [5, 6]. These linkage studies were quickly followed by the identification of the first


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