title: Biochemical characterization of novel glucokinase mutations isolated from Spanish maturity-onset diabetes of the young (MODY2) patients.
abstract: Mature-onset diabetes of the young, type 2 (MODY2) is associated with mutations in the glucokinase (GCK) gene that result in impaired glucokinase activity. Although more than 200 inactivating GCK mutations have been reported, only less than 20% of these mutations have been functionally characterized. In this work, we describe the biochemical characterization of six missense glucokinase mutations associated with MODY2 from Spanish patients, namely, Y61S, V182L, C233R, E265K, A379V, and K420E. All these mutations produced enzymes that presented reduced enzymatic activity in various degrees, from a mild affectation (K420E) to a more severe effect (C233R). Mutation severity correlated with the importance of the structural changes introduced by the mutations. For example, C233R affected a critical residue of the active center of the enzyme and rendered a protein with undetectable enzymatic activity. These data add new information on the structure-function relationship of human glucokinase.
authors.affiliation: Endocrinology and Diabetes Research Group, Hospital de Cruces and University of Basque Country, Bizkaia, Basque Country, Spain.
authors.forename: Itziar
authors.initials: I
authors.lastname: Estalella
authors.affiliation: Instituto de Biomedicina de Valencia (CSIC) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Jaime Roig 11, 46010, Valencia, Spain.
authors.forename: Maria Adelaida
authors.initials: MA
authors.lastname: Garcia-Gimeno
authors.affiliation: Instituto de Biomedicina de Valencia (CSIC) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Jaime Roig 11, 46010, Valencia, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Marina
authors.affiliation: Endocrinology and Diabetes Research Group, Hospital de Cruces and University of Basque Country, Bizkaia, Basque Country, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Castaño
authors.affiliation: Instituto de Biomedicina de Valencia (CSIC) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Jaime Roig 11, 46010, Valencia, Spain. sanz@ibv.csic.es.
authors.forename: Pascual
authors.initials: P
authors.lastname: Sanz
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D019943:Amino Acid Substitution / Q000235:genetics*; D002648:Child; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics*; D005941:Glucokinase / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D007700:Kinetics; D008875:Middle Aged; D020125:Mutation, Missense; D011487:Protein Conformation; D012720:Severity of Illness Index; D013030:Spain
chemical_list: D005941:Glucokinase