Opposite Clinical Phenotypes of “Glucokinase Disease”: Description of a Novel Activating Mutation and Contiguous Inactivating Mutations in Human Glucokinase Gene

Glucokinase (GK) is essential for glucose-stimulated insulin release from pancreatic β-cell, serving as glucose sensor in humans. Inactivating or activating mutations of glucokinase lead to different forms of “Glucokinase Disease”, i.e. Monogenic Diabetes of Youth (GCK-MDY), Permanent Neonatal Diabetes (inactivating mutations) and Congenital Hyperinsulinism, respectively. Here we present a novel GCK activating mutation (p.E442K) found in an infant with neonatal hypoglycemia (1.5 mmol/l) and in two other family members suffering from recurrent hypoglycemic episodes in their childhood and adult life. In contrast to the severe clinical presentation in the index case, functional studies showed only a slight activation of the protein (relative activity index of 3.3). We also report on functional studies of two inactivating mutations of the GCK (p.E440G and p.S441W), contiguous to the activating one, that lead to GCK-MDY. Interestingly, adult family members carrying the GCK pE440G mutation show an unusually “heterogeneous and progressive” diabetic phenotype, a feature not typical of MDY. In summary, we identified a novel activating GCK mutation that although being associated with severe neonatal hypoglycemia is characterized by the mildest activation of the glucokinase enzyme of all previously reported.