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Title: | Opposite clinical phenotypes of glucokinase disease: Description of a novel activating mutation and contiguous inactivating mutations in human glucokinase (GCK) gene. |
Authors: | Barbetti, Fabrizio Cobo-Vuilleumier, Nadia Dionisi-Vici, Carlo Toni, Sonia Ciampalini, Paolo Massa, Ornella Rodriguez-Bada, Pablo Colombo, Carlo Lenzi, Lorenzo Garcia-Gimeno, María A Bermudez-Silva, Francisco J Rodriguez de Fonseca, Fernando Banin, Patrizia Aledo, Juan C Baixeras, Elena Sanz, Pascual Cuesta-Muñoz, Antonio L |
metadata.dc.contributor.authoraffiliation: | [Barbetti,F; Dionisi-Vici,C; Ciampalini,P; Massa,O; Colombo,C] Bambino Gesú Pediatric Hospital Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy. [Barbetti,F] Department of Internal Medicine, University of Rome Tor Vergata, Rome, Italy. Laboratory of Molecular Endocrinology and Metabolism, S Raffaele Biomedical Park Foundation, Rome, Italy. [Cobo-Vuilleumier,N; Rodriguez-Bada,P; Bermudez-Silva,FJ; Rodriguez de Fonseca,F; Aledo,JC; Baixeras,E; Cuesta-Muñoz,AL] Center for the Study of Pancreatic-Cell Diseases. Instituto Mediterráneo para el Avance de la Biotecnología y la Investigación Sanitaria Foundation and Carlos Haya Hospital, Málaga, Spain. [Toni,S; Lenzi,L] Regional Center for Juvenile Diabetes, Meyer Pediatric Hospital, Florence, Italy. [Garcia-Gimeno,MA; Sanz,P] Institute of Biomedicine of Valencia (CSIC). CIBERER-ISCIII, Valencia, Spain. [Banin,P] Pediatric and Adolescent Unit, S. Anna Hospital, Ferrara, Italy. [Aledo,JC] Molecular Biology and Biochemistry Department University of Málaga, Spain. |
Keywords: | Femenino;Predisposición Genética a la Enfermedad;Humanos;Hipoglucemia;Glucoquinasa;Recién Nacido;Cinética;Masculino;Modelos Teóricos;Mutagénesis Sitio-Dirigida;Mutación;Linaje;Fenotipo |
metadata.dc.subject.mesh: | Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genotype::Genetic Predisposition to Disease Medical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases (Alcohol Group Acceptor)::Glucokinase Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans Medical Subject Headings::Diseases::Nutritional and Metabolic Diseases::Metabolic Diseases::Glucose Metabolism Disorders::Hypoglycemia Medical Subject Headings::Named Groups::Persons::Age Groups::Infant::Infant, Newborn Medical Subject Headings::Phenomena and Processes::Physical Phenomena::Mechanical Phenomena::Kinetics Medical Subject Headings::Check Tags::Male Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Models, Theoretical Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Genetic Engineering::Protein Engineering::Mutagenesis, Site-Directed Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Variation::Mutation Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Pedigree Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Phenotype Medical Subject Headings::Check Tags::Female |
Issue Date: | Dec-2009 |
Publisher: | The Endocrine Society |
Citation: | Barbetti 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):1983-9 |
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. |
Description: | Journal Article; Research Support, Non-U.S. Gov't; |
URI: | http://hdl.handle.net/10668/503 |
metadata.dc.relation.publisherversion: | http://mend.endojournals.org/content/23/12/1983.abstract |
metadata.dc.identifier.doi: | 10.1210/me.2009-0094 |
ISSN: | 0888-8809 (Print) 1944-9917 (Online) |
Appears in Collections: | 01- Artículos - Hospital Regional de Málaga 01- Artículos - IBIMA. Instituto de Investigación Biomédica de Málaga |
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Barbetti_OppositeClinicalPhenotypes.pdf | Artículo publicado | 311,99 kB | Adobe PDF | View/Open |
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