title: Opposite clinical phenotypes of glucokinase disease: Description of a novel activating mutation and contiguous inactivating mutations in human glucokinase (GCK) gene.
abstract: Glucokinase is essential for glucose-stimulated insulin release from the pancreatic beta-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.
authors.affiliation: Bambino Gesú Pediatric Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy. fabrizio.barbetti@spr-r.it
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Barbetti
authors.forename: Nadia
authors.initials: N
authors.lastname: Cobo-Vuilleumier
authors.forename: Carlo
authors.initials: C
authors.lastname: Dionisi-Vici
authors.forename: Sonia
authors.initials: S
authors.lastname: Toni
authors.forename: Paolo
authors.initials: P
authors.lastname: Ciampalini
authors.forename: Ornella
authors.initials: O
authors.lastname: Massa
authors.forename: Pablo
authors.initials: P
authors.lastname: Rodriguez-Bada
authors.forename: Carlo
authors.initials: C
authors.lastname: Colombo
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Lenzi
authors.forename: María A
authors.initials: MA
authors.lastname: Garcia-Gimeno
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Bermudez-Silva
authors.forename: Fernando
authors.initials: F
authors.lastname: Rodriguez de Fonseca
authors.forename: Patrizia
authors.initials: P
authors.lastname: Banin
authors.forename: Juan C
authors.initials: JC
authors.lastname: Aledo
authors.forename: Elena
authors.initials: E
authors.lastname: Baixeras
authors.forename: Pascual
authors.initials: P
authors.lastname: Sanz
authors.forename: Antonio L
authors.initials: AL
authors.lastname: Cuesta-Muñoz
mesh_terms: D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005941:Glucokinase / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007003:Hypoglycemia / Q000235:genetics; D007231:Infant, Newborn; D007700:Kinetics; D008297:Male; D008962:Models, Theoretical; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype
chemical_list: D005941:Glucokinase