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Opposite Clinical Phenotypes of Glucokinase Disease: Description of a Novel Activating Mutation and Contiguous Inactivating Mutations in Human Glucokinase (GCK) Gene

Bambino Gesù Pediatric Hospital (F.B., C.D.-V., P.C., O.M., C.C.), Istituto di Ricovero e Cura a Carattere Scientifico, Rome 00164, Italy; Department of Internal Medicine (F.B.), University of Rome Tor Vergata, Rome 00134, Italy; Laboratory of Molecular Endocrinology and Metabolism (F.B.), S Raffaele Biomedical Park Foundation, Rome 00128, Italy; Center for the Study of Pancreatic β-Cell Diseases (N.C.-V., P.R.-B., F.J.B.-S., F.R.d.F., J.C.A., E.B., A.L.C.-M.). Instituto Mediterráneo para el Avance de la Biotecnología y la Investigación Sanitaria Foundation and Carlos Haya Hospital, Málaga 29010, Spain; Regional Center for Juvenile Diabetes (S.T., L.L.), Meyer Pediatric Hospital, Florence 50132, Italy; Institute of Biomedicine of Valencia (CSIC) and CIBERER-ISCIII (M.A.G.-G., P.S.), Valencia 46010, Spain; Pediatric and Adolescent Unit (P.B.), S. Anna Hospital, Ferrara, Italy; and Molecular Biology and Biochemistry Department (J.C.A.). University of Málaga, Málaga 29071, Spain

Address all correspondence and requests for reprints to: Fabrizio Barbetti, M.D., Ph.D., Tor Vergata University Hospital, Laboratory Medicine, First floor, Section D, Room 118, Viale Oxford 81, 00134 Rome, Italy. E-mail: mody.2{at}libero.it or fabrizio.barbetti{at}spr-r.it; and Antonio Cuesta-Munoz, M.D., Ph.D., Center for the Study of Pancreatic β-Cell Diseases. IMABIS Foundation and Carlos Haya Hospital. Avda. Carlos Haya 82, Pabellón A-7^a planta 29010 Málaga, Spain. E-mail: alcm{at}fundacionimabis.org.

Glucokinase is essential for glucose-stimulated insulin release from the pancreatic β-cell, serving as glucose sensor in humans. Inactivating or activating mutations of glucokinase lead to different forms of glucokinase disease, i.e. GCK-monogenic diabetes of youth, permanent neonatal diabetes (inactivating mutations), and congenital hyperinsulinism, respectively. Here we present a novel glucokinase gene (GCK)-activating mutation (p.E442K) found in an infant with neonatal hypoglycemia (1.5 mmol/liter) 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 monogenic diabetes of youth. Interestingly, adult family members carrying the GCK pE440G mutation show an unusually heterogeneous and progressive diabetic phenotype, a feature not typical of GCK-monogenic diabetes of youth. 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.