Opposite clinical phenotypes of glucokinase disease: Description of a novel activating mutation and contiguous inactivating mutations in human glucokinase (GCK) gene.

Barbetti, FabrizioCobo-Vuilleumier, NadiaDionisi-Vici, CarloToni, SoniaCiampalini, PaoloMassa, OrnellaRodriguez-Bada, PabloColombo, CarloLenzi, LorenzoGarcia-Gimeno, María ABermudez-Silva, Francisco JRodriguez de Fonseca, FernandoBanin, PatriziaAledo, Juan CBaixeras, ElenaSanz, PascualCuesta-Muñoz, Antonio L2012-09-282012-09-282009-12Barbetti F, Cobo-Vuilleumier N, Dionisi-Vici C, Toni S, Ciampalini P, Massa O, et al. Opposite clinical phenotypes of glucokinase disease: Description of a novel activating mutation and contiguous inactivating mutations in human glucokinase (GCK) gene. Mol. Endocrinol.. 2009 Dec; 23(12):1983-90888-8809http://hdl.handle.net/10668/503Journal Article; Research Support, Non-U.S. Gov't;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.enFemeninoPredisposición Genética a la EnfermedadHumanosHipoglucemiaGlucoquinasaRecién NacidoCinéticaMasculinoModelos TeóricosMutagénesis Sitio-DirigidaMutaciónLinajeFenotipoMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genotype::Genetic Predisposition to DiseaseMedical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases (Alcohol Group Acceptor)::GlucokinaseMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::HumansMedical Subject Headings::Diseases::Nutritional and Metabolic Diseases::Metabolic Diseases::Glucose Metabolism Disorders::HypoglycemiaMedical Subject Headings::Named Groups::Persons::Age Groups::Infant::Infant, NewbornMedical Subject Headings::Phenomena and Processes::Physical Phenomena::Mechanical Phenomena::KineticsMedical Subject Headings::Check Tags::MaleMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Models, TheoreticalMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Genetic Engineering::Protein Engineering::Mutagenesis, Site-DirectedMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Variation::MutationMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::PedigreeMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::PhenotypeMedical Subject Headings::Check Tags::FemaleOpposite clinical phenotypes of glucokinase disease: Description of a novel activating mutation and contiguous inactivating mutations in human glucokinase (GCK) gene.research article19884385open access10.1210/me.2009-00941944-9917