title: Glucokinase gene mutations: structural and genotype-phenotype analyses in MODY children from South Italy.
abstract: BACKGROUND
  Maturity onset diabetes of the young type 2 (or GCK MODY) is a genetic form of diabetes mellitus provoked by mutations in the glucokinase gene (GCK).
  
  
  RESULTS
  We screened the GCK gene by direct sequencing in 30 patients from South Italy with suspected MODY. The mutation-induced structural alterations in the protein were analyzed by molecular modeling. The patients' biochemical, clinical and anamnestic data were obtained. Mutations were detected in 16/30 patients (53%); 9 of the 12 mutations identified were novel (p.Glu70Asp, p.Phe123Leu, p.Asp132Asn, p.His137Asp, p.Gly162Asp, p.Thr168Ala, p.Arg392Ser, p.Glu290X, p.Gln106_Met107delinsLeu) and are in regions involved in structural rearrangements required for catalysis. The prevalence of mutation sites was higher in the small domain (7/12: approximately 59%) than in the large (4/12: 33%) domain or in the connection (1/12: 8%) region of the protein. Mild diabetic phenotypes were detected in almost all patients [mean (SD) OGTT = 7.8 mMol/L (1.8)] and mean triglyceride levels were lower in mutated than in unmutated GCK patients (p = 0.04).
  
  
  CONCLUSIONS
  The prevalence of GCK MODY is high in southern Italy, and the GCK small domain is a hot spot for MODY mutations. Both the severity of the GCK mutation and the genetic background seem to play a relevant role in the GCK MODY phenotype. Indeed, a partial genotype-phenotype correlation was identified in related patients (3 pairs of siblings) but not in two unrelated children bearing the same mutation. Thus, the molecular approach allows the physician to confirm the diagnosis and to predict severity of the mutation.
authors.affiliation: Dipartimento di Biochimica e Biotecnologie Mediche, Università di Napoli Federico II and CEINGE Biotecnologie Avanzate, Napoli, Italia.
authors.forename: Nadia
authors.initials: N
authors.lastname: Tinto
authors.forename: Adriana
authors.initials: A
authors.lastname: Zagari
authors.forename: Marina
authors.initials: M
authors.lastname: Capuano
authors.forename: Alfonso
authors.initials: A
authors.lastname: De Simone
authors.forename: Valentina
authors.initials: V
authors.lastname: Capobianco
authors.forename: Gerardo
authors.initials: G
authors.lastname: Daniele
authors.forename: Michela
authors.initials: M
authors.lastname: Giugliano
authors.forename: Raffaella
authors.initials: R
authors.lastname: Spadaro
authors.forename: Adriana
authors.initials: A
authors.lastname: Franzese
authors.forename: Lucia
authors.initials: L
authors.lastname: Sacchetti
mesh_terms: D000293:Adolescent; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D003924:Diabetes Mellitus, Type 2 / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D005838:Genotype; D005941:Glucokinase / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D007223:Infant; D007558:Italy; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype
chemical_list: D005941:Glucokinase